Advertisement

Peroxisome Proliferator-Activated Receptors and Their Agonists in Nonalcoholic Fatty Liver Disease

      Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. In addition to the liver-related morbidity and mortality, NAFLD is now also associated with various extrahepatic diseases. Pathogenesis of NAFLD is multifactorial with limited pharmacotherapy options for the treatment of patients with NAFLD. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in the transcriptional regulation of lipid metabolism, glucose homeostasis, energy balance, inflammation, and atherosclerosis. PPAR agonists are attractive options for treatment of NAFLD as they can act at multiple targets involved in the pathogenesis of NAFLD. We reviewed the available literature on the pathophysiological role of PPARs and use of PPAR agonists in the treatment of NAFLD. Original studies and review articles available on PubMed regarding the role of PPARs in the pathogenesis and utility of PPAR agonists in the treatment of NAFLD were included in this review article. ClinicalTrials.gov and Clinical Trials Registry-India sites were searched for ongoing studies on saroglitazar. The available literature suggests that PPARs play an important role in the pathogenesis of NAFLD. Use of PPAR gamma agonists is associated with histological improvement in NAFLD. Dual PPAR agonists with no or minimal PPAR gamma activity are being explored in the treatment of NAFLD. Because of the pathophysiological role of PPARs in NAFLD, PPAR agonists are attractive options for the treatment of patients with NAFLD. Dual PPAR agonists without significant gamma activity appear promising for the treatment of NAFLD.

      Keywords

      Abbreviations:

      CPT-1 (Carnitine palmitoyltransferase-1), MPC (mitochondrial pyruvate carrier), NAFLD (nonalcoholic fatty liver disease), NASH (Nonalcoholic steatohepatitis), NF-κB (nuclear factor-kappa beta), OR (odds ratio), PPAR (Peroxisome proliferator-activated receptors), RXR (retinoid X receptor), TZDs (thiazolidinediones)
      Peroxisome proliferator-activated receptors (PPARs) are a ligand-activated transcription factor belonging to a nuclear receptor subfamily that is involved in the transcriptional regulation of lipid metabolism, glucose homeostasis, energy balance, inflammation, and atherosclerosis. There are three PPAR isoforms, alpha (α), beta (β)/delta (δ), and gamma (γ), which are differentially expressed in various tissues.
      • Ahmed W.
      • Ziouzenkova O.
      • Brown J.
      • et al.
      PPARs and their metabolic modulation: new mechanisms for transcriptional regulation?.
      • Poulsen L.
      • Siersbaek M.
      • Mandrup S.
      PPARs: fatty acid sensors controlling metabolism.
      PPARα is expressed ubiquitously but is largely present in the liver. PPARβ/δ is expressed mainly in skeletal muscles and to a lesser degree in adipose tissue and skin. PPARγ is highly expressed in adipose tissue (Table 1).
      • Grygiel-Górniak B.
      Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review.
      • Pawlak M.
      • Lefebvre P.
      • Staels B.
      Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease.
      • Tailleux A.
      • Wouters K.
      • Staels B.
      Roles of PPARs in NAFLD: potential therapeutic targets.
      • Corton J.C.
      Evaluation of the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver tumor induction by trichloroethylene and metabolites.
      • Fisher C.D.
      • Jackson J.P.
      • Lickteig A.J.
      • Augustine L.M.
      • Cherrington N.J.
      Drug metabolizing enzyme induction pathways in experimental non-alcoholic steatohepatitis.
      • Takeuchi S.
      • Matsuda T.
      • Kobayashi S.
      • Takahashi T.
      • Kojima H.
      In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma and quantitative analysis of in vivo induction pathway.
      Table 1Types and Actions of PPARs (Based on Grygiel-Górniak et al
      • Grygiel-Górniak B.
      Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review.
      , Pawlak et al
      • Pawlak M.
      • Lefebvre P.
      • Staels B.
      Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease.
      , Tailleux et al
      • Tailleux A.
      • Wouters K.
      • Staels B.
      Roles of PPARs in NAFLD: potential therapeutic targets.
      , Corton
      • Corton J.C.
      Evaluation of the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver tumor induction by trichloroethylene and metabolites.
      , Fisher et al
      • Fisher C.D.
      • Jackson J.P.
      • Lickteig A.J.
      • Augustine L.M.
      • Cherrington N.J.
      Drug metabolizing enzyme induction pathways in experimental non-alcoholic steatohepatitis.
      , and Fisher et al
      • Takeuchi S.
      • Matsuda T.
      • Kobayashi S.
      • Takahashi T.
      • Kojima H.
      In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma and quantitative analysis of in vivo induction pathway.
      ).
      TypeTissue distribution
      Tissues in bold fonts indicate main tissue expression.
      Gene targetsNatural ligandSynthetic agonistsEffect
      PPARαLiver

      Muscle

      Heart

      Kidney
      Β oxidation

      Fatty acid transport protein

      Fatty acid translocase

      Lipoprotein lipase

      Apolipoprotein A-I and A-II

      Sterol 12-hydroxylase
      Unsaturated fatty acids

      Leukotriene B4

      8-Hydroxyeicosatetraenoic acid
      Gemfibrozil

      Fenofibrate

      Clofibrate
      Fatty acid oxidation

      Anti-inflammatory
      PPARβ/δUbiquitous, muscle, gastrointestinal, adipose tissue

      Macrophages

      Heart
      Genes involved in lipid uptake, metabolism, and efflux (repressed by PPARs)Unsaturated fatty acids

      Carbaprostacyclin

      Components of VLDL
      GW501516

      GW0742

      MBX-8025
      Glucose homeostasis, insulin sensitivity
      PPARγAdipose tissue

      Liver, kidney, intestine
      Fatty acid–binding protein (aP2)

      Fatty acid transport protein

      Fatty acid translocase
      Unsaturated fatty acids, 15-hydroxyeicosatetraenoic acid, 9- and 13- hydroxyoctadecadienoic acid, 15-deoxy-12,14-prostaglandin J2, prostaglandin PGJ2ThiazolidinedionesAdipogenesis

      Insulin sensitization, glucose homeostasis

      Fatty acid oxidation
      PPAR, peroxisome proliferator-activated receptor; VLDL, very low-density lipoprotein.
      bAll tissues not shown.
      a Tissues in bold fonts indicate main tissue expression.
      Free fatty acids (FAs), eicosanoids, and various complex lipids are considered endogenous PPAR ligands. Exogenous ligands are environmental and pharmaceutical molecules that can activate various PPAR family receptors to varying degrees.
      • Corton J.C.
      Evaluation of the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver tumor induction by trichloroethylene and metabolites.
      • Fisher C.D.
      • Jackson J.P.
      • Lickteig A.J.
      • Augustine L.M.
      • Cherrington N.J.
      Drug metabolizing enzyme induction pathways in experimental non-alcoholic steatohepatitis.
      • Takeuchi S.
      • Matsuda T.
      • Kobayashi S.
      • Takahashi T.
      • Kojima H.
      In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma and quantitative analysis of in vivo induction pathway.
      • Laughter A.R.
      • Dunn C.S.
      • Swanson C.L.
      • Howroyd P.
      • Cattley R.C.
      • Corton J.C.
      Role of the peroxisome proliferator-activated receptor alpha (PPARalpha) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver.
      PPARs form a heterodimer with the retinoid X receptor (RXR) after binding to the ligand and bind to response elements that regulate the expression of genes encoding proteins involved in beta oxidation, FA uptake, adipogenesis, and adipocyte differentiation.
      • Grygiel-Górniak B.
      Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review.
      • Evans R.M.
      • Barish G.D.
      • Wang Y.X.
      PPARs and the complex journey to obesity.
      • Desvergne B.
      • Wahli W.
      Peroxisome proliferator-activated receptors: nuclear control of metabolism.
      • Issemann I.
      • Green S.
      Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.
      PPAR ligands have emerged as potential therapeutics for nonalcoholic fatty liver disease (NAFLD) (Table 1).
      NAFLD has emerged as the most common liver disease in the world, including Asia Pacific, and is responsible for significant liver disease burden.
      • Duseja A.
      • Najmy S.
      • Sachdev S.
      • et al.
      High prevalence of non-alcoholic fatty liver disease among healthy male blood donors of urban India.
      • Duseja A.
      • Sharma B.
      • Kumar A.
      • et al.
      Nonalcoholic fatty liver in a developing country is responsible for significant liver disease.
      The spectrum of NAFLD ranges from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), which has the propensity to progress on to cirrhosis of the liver and hepatocellular carcinoma.
      • Duseja A.
      • Singh S.P.
      • Saraswat V.A.
      • et al.
      Non-alcoholic fatty liver disease and metabolic syndrome-position paper of the Indian national association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology.
      NAFLD is characterized by presence of insulin resistance, dyslipidemia, and a proinflammatory state. The mainstay of current treatment of NAFLD is weight loss by lifestyle modification, which is difficult to achieve and sustain for most of the patients. There are limited pharmacotherapy options, and the focus of treatment has largely been on patients with progressive NASH.
      • Duseja A.
      • Singh S.P.
      • Saraswat V.A.
      • et al.
      Non-alcoholic fatty liver disease and metabolic syndrome-position paper of the Indian national association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology.
      PPARs affect glucose homeostasis (insulin-sensitizing properties), inflammation, and atherogenesis and control dyslipidemia. Thus, these agents should act at multiple levels in NAFLD pathogenesis, which makes them an attractive target for drug development.

      PPARα and its agonists

      PPARα is expressed in many mammalian cells and tissues such as the liver, kidney, heart, muscle, adipose tissue, and others including immune cells (e.g., macrophages).
      • Tyagi S.
      • Gupta P.
      • Saini A.S.
      • Kaushal C.
      • Sharma S.
      The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases.
      PPARα plays a role in multiple regulatory functions. In the liver, it plays a crucial role in FA oxidation, which provides energy for peripheral tissues, and has a potential role in the oxidant/antioxidant pathway.
      • Lefebvre P.
      • Chinetti G.
      • Fruchart J.C.
      • Staels B.
      Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis.
      PPARα also has anti-inflammatory effects through complex regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).
      • Vanden Berghe W.
      • Vermeulen L.
      • Delerive P.
      • De Bosscher K.
      • Staels B.
      • Haegeman G.
      A paradigm for gene regulation: inflammation, NF-kappaB and PPAR.
      The activation of PPARα occurs after dimerization with the RXR, resulting in formation of a multiprotein complex with protein coactivators. After activation, PPARα binds to responsive elements in DNA, resulting in the transcription of various anti-inflammatory proteins, such as the kB-α inhibitor.
      • Delerive P.
      • Gervois P.
      • Fruchart J.C.
      • Staels B.
      Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators.
      Carnitine palmitoyltransferase 1 (CPT-1) is a pivotal enzyme that allows the FA to go through the inner mitochondrial membrane and reach the mitochondrial matrix for further metabolism.
      • Serviddio G.
      • Giudetti A.M.
      • Bellanti F.
      • et al.
      Oxidation of hepatic carnitine palmitoyl transferase-I (CPT-I) impairs fatty acid beta-oxidation in rats fed a methionine-choline deficient diet.
      Reduction of PPARα expression in the liver causes impairment of the transcription of its target gene CPT-1, and excessive FAs tend to accumulate in the form of triglycerides.
      • Yu G.S.
      • Lu Y.C.
      • Gulick T.
      Co-regulation of tissue-specific alternative human carnitine palmitoyltransferase Ibeta gene promoters by fatty acid enzyme substrate.
      • Brandt J.M.
      • Djouadi F.
      • Kelly D.P.
      Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha.
      PPARα acts as a nutritional sensor, which allows adaptation of the rates of FA oxidation, lipogenesis, and ketone body synthesis, in response to feeding and fasting.
      • Hashimoto T.
      • Cook W.S.
      • Qi C.
      • Yeldandi A.V.
      • Reddy J.K.
      • Rao M.S.
      Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting.
      During excessive dietary intake of lipids, hepatic PPARα expression decreases.
      • Fraulob J.C.
      • Souza-Mello V.
      • Aguila M.B.
      • Mandarim-de-Lacerda C.A.
      Beneficial effects of rosuvastatin on insulin resistance, adiposity, inflammatory markers and non-alcoholic fatty liver disease in mice fed on a high-fat diet.
      • Souza-Mello V.
      • Gregorio B.M.
      • Cardoso-de-Lemos F.S.
      • de Carvalho L.
      • Aguila M.B.
      • Mandarim-de-Lacerda C.A.
      Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet.
      Studies in mice with genetic deletion of PPARα (PPARα−/−) and high-fat diet resulted in accumulation of more hepatic triglycerides with a significantly higher NAFLD activity score (NAS) compared with wild-type (WT) controls.
      • Stienstra R.
      • Mandard S.
      • Patsouris D.
      • Maass C.
      • Kersten S.
      • Muller M.
      Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation.
      • Patsouris D.
      • Reddy J.K.
      • Muller M.
      • Kersten S.
      Peroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression.
      Mice with the PPARα gene knockout, fed with a high-fat diet, also showed increased markers of oxidative stress, inflammation, and cell death.
      • Abdelmegeed M.A.
      • Yoo S.H.
      • Henderson L.E.
      • Gonzalez F.J.
      • Woodcroft K.J.
      • Song B.J.
      PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver.
      Natural agonists of PPARs include FAs, eicosanoids, and phospholipids derived from cellular FA metabolism or from dietary lipids. The synthetic ligands include fibrates, thiazolidinediones (TZDs), glitazars, elafibranor, and several others.
      • Tan C.K.
      • Zhuang Y.
      • Wahli W.
      Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome.
      In the mice model, the PPARα agonist Wy-14643 prevented methionine and choline deficient (MCD) diet-induced hepatic triglyceride accumulation in WT mice, but it had no effect on PPARα−/− mice.
      • Ip E.
      • Farrell G.C.
      • Robertson G.
      • Hall P.
      • Kirsch R.
      • Leclercq I.
      Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice.
      Fibrates are considered PPARα agonists, although less potent than the PPARα agonist Wy-14643. Several studies have shown improvement of biochemical or histological parameters with fibrates in patients with NAFLD.
      • Fernandez-Miranda C.
      • Perez-Carreras M.
      • Colina F.
      • Lopez-Alonso G.
      • Vargas C.
      • Solis-Herruzo J.A.
      A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease.
      • Basaranoglu M.
      • Acbay O.
      • Sonsuz A.
      A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis.
      • El-Haggar S.M.
      • Mostafa T.M.
      Comparative clinical study between the effect of fenofibrate alone and its combination with pentoxifylline on biochemical parameters and liver stiffness in patients with non-alcoholic fatty liver disease.
      Fibrates, however, have limited clinical efficacy because they are weak PPARα agonists and have significant adverse events. Fernandez-Miranda et al used 200 mg/day fenofibrate for 48 weeks in a series of 16 patients with NAFLD. The authors noted a significant decrease in levels of triglycerides, glucose, and gamma-glutamyl transpeptidase and proportion of patients with raised transaminases or metabolic syndrome and a trend of decreasing insulin resistance. The repeat biopsy at the end of the study showed decreased ballooning, but other histologic parameters did not improve significantly.
      • Fernandez-Miranda C.
      • Perez-Carreras M.
      • Colina F.
      • Lopez-Alonso G.
      • Vargas C.
      • Solis-Herruzo J.A.
      A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease.
      El-Haggar et al compared fenofibrate with fenofibrate plus pentoxifylline for 24 weeks. The addition of pentoxifylline to fenofibrate did not improve lipid parameters, but a beneficial effect on indirect markers of hepatic fibrosis, inflammation, insulin resistance, and liver stiffness was present.
      • El-Haggar S.M.
      • Mostafa T.M.
      Comparative clinical study between the effect of fenofibrate alone and its combination with pentoxifylline on biochemical parameters and liver stiffness in patients with non-alcoholic fatty liver disease.
      Laurin et al
      • Laurin J.
      • Lindor K.D.
      • Crippin J.S.
      • et al.
      Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.
      compared clofibrate with ursodeoxycholic acid in a 1-year study. The authors could not find any advantage of clofibrate in patients with NAFLD. Newer selective PPARα-specific agonists, known as selective PPARα modulators, are in different phases of development.
      • Ishibashi S.
      • Yamashita S.
      • Arai H.
      • et al.
      Effects of K-877, a novel selective PPARalpha modulator (SPPARMalpha), in dyslipidaemic patients: a randomized, double blind, active- and placebo-controlled, phase 2 trial.
      • Araujo S.
      • Soares E.S.A.
      • Gomes F.
      • et al.
      Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease (NAFLD).

      PPARβ/δ and its agonists

      PPARβ/δ is the least studied among all the PPAR isotypes, although it has significant expression in tissues controlling lipid metabolism, such as adipocytes, heart, skeletal muscle, liver, and macrophages.
      • Gross B.
      • Staels B.
      PPAR agonists: multimodal drugs for the treatment of type-2 diabetes.
      In the liver, PPARβ/δ is well expressed in hepatocytes but is also expressed in Kupffer cells and hepatic stellate cells, suggesting a potential role in inflammation and fibrosis.
      • Odegaard J.I.
      • Ricardo-Gonzalez R.R.
      • Goforth M.H.
      • et al.
      Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.
      The PPARβ/δ agonist, GW501516, has been shown to ameliorate obesity and insulin resistance in rats.
      • Tanaka T.
      • Yamamoto J.
      • Iwasaki S.
      • et al.
      Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome.
      In a small 2-week pilot trial on six subjects, it was found by magnetic resonance imaging that GW501516 resulted in reduction of liver fat along with reduction in serum triglycerides and low-density lipoprotein cholesterol.
      • Riserus U.
      • Sprecher D.
      • Johnson T.
      • et al.
      Activation of peroxisome proliferator-activated receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men.
      However, clinical development of GW501516 was abandoned owing to development of cancer in preclinical models.
      • Peters J.M.
      • Gonzalez F.J.
      • Muller R.
      Establishing the role of PPARbeta/delta in carcinogenesis.
      Another PPARβ/δ agonist, GW0742, improved insulin signaling and reduced hepatic steatosis in a rat model.
      • Lee M.Y.
      • Choi R.
      • Kim H.M.
      • et al.
      Peroxisome proliferator-activated receptor δ agonist attenuates hepatic steatosis by anti-inflammatory mechanism.
      In a study using GW0742, the activation of PPARβ/δ was found to inhibit CCl4-induced liver toxicity through the PPARβ/δ-dependent downregulation of proinflammatory signaling through interactions between PPARβ/δ and NF-κB.
      • Shan W.
      • Palkar P.S.
      • Murray I.A.
      • et al.
      Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression.
      A novel PPARβ/δ agonist, MBX-8025, was evaluated in a randomized, double-blind, placebo-controlled study. The study included overweight subjects with dyslipidemia and found that treatment with MBX-8025 (seladelpar) resulted in favorable lipid profiles and decreased liver enzymes.
      • Bays H.E.
      • Schwartz S.
      • Littlejohn 3rd, T.
      • et al.
      MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin.
      In a randomized study of MBX-8025 versus vehicle (1% methylcellulose), MBX-8025 normalized hyperglycemia, hyperinsulinemia, and glucose disposal in foz/foz mice. MBX-8025 reduced alanine aminotransferase and normalized serum lipids. There was significantly less steatosis, inflammation, ballooning, apoptosis, and fibrosis in the MBX-8025 arm.
      • Haczeyni F.
      • Wang H.
      • Barn V.
      • et al.
      The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice.
      At this time, data regarding effectiveness of PPARβ/δ in treatment of NAFLD are limited to derive any conclusion.

      PPARγ and its agonists

      PPARγ is most highly expressed in adipose tissue, where it serves an important role in the regulation of adipocyte differentiation, adipogenesis, and lipid metabolism.
      • Zhu Y.
      • Alvares K.
      • Huang Q.
      • Rao M.S.
      • Reddy J.K.
      Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver.
      In an animal model of NASH, Zhong and Liu
      • Zhong X.
      • Liu H.
      Honokiol attenuates diet-induced non-alcoholic steatohepatitis by regulating macrophage polarization through activating peroxisome proliferator-activated receptor gamma.
      showed that the activation of PPARγ regulates the polarization of the macrophages to M2 subtype. Kupffer cells have proinflammatory (M1) and anti-inflammatory (M2) subtypes; thus, change toward the M2 subtype may prevent development of NAFLD.
      • Zhong X.
      • Liu H.
      Honokiol attenuates diet-induced non-alcoholic steatohepatitis by regulating macrophage polarization through activating peroxisome proliferator-activated receptor gamma.
      TZDs are the most widely investigated PPARγ agonists. TZDs represent a class of clinically used insulin-sensitizing drugs, which currently include rosiglitazone and pioglitazone. TZDs promote the uptake and storage of FAs in adipose tissue, increasing adipose tissue mass while sparing the skeletal muscle and the liver.
      • Yki-Jarvinen H.
      Thiazolidinediones.
      In an animal model of NASH induced with a choline–methionine–deficient diet, rosiglitazone prevented the development of NASH.
      • Nan Y.M.
      • Fu N.
      • Wu W.J.
      • et al.
      Rosiglitazone prevents nutritional fibrosis and steatohepatitis in mice.
      In another animal model, Deng et al
      • Deng W.
      • Meng Z.
      • Sun A.
      • Yang Z.
      Pioglitazone suppresses inflammation and fibrosis in nonalcoholic fatty liver disease by down-regulating PDGF and TIMP-2: evidence from in vitro study.
      demonstrated that pioglitazone has anti-inflammatory and antifibrotic effects by repressing the expression level of platelet-derived growth factor and tissue inhibitor of metalloproteinase-2.
      Caldwell et al reported data of troglitazone treatment in 10 female patients with histological NASH including 3 with compensated cirrhosis. Troglitazone was given for ≤6 months. A repeat biopsy in responders (normal alanine aminotransferase (ALT) at the end of treatment) showed persistence of NASH in all; four patients had one-point improvement of necroinflammation.
      • Caldwell S.H.
      • Hespenheide E.E.
      • Redick J.A.
      • Iezzoni J.C.
      • Battle E.H.
      • Sheppard B.L.
      A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.
      Troglitazone was associated with serious hepatotoxicity and was banned later.
      • Masubuchi Y.
      Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review.
      Ratziu et al
      • Ratziu V.
      • Giral P.
      • Jacqueminet S.
      • et al.
      Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial.
      studied the role of rosiglitazone in a randomized controlled trial (RCT) called the FLIRT trial. Thirty-two patients on rosiglitazone were compared with 31 patients on placebo. The rosiglitazone arm had improved steatosis (47% vs 16%) and transminases (38% vs 7%) at the end of 1 year as compared with the placebo arm. There was no improvement in fibrosis and the NAFLD activity score. Weight gain happened significantly in the rosiglitazone arm, and dose reduction/discontinuation happened in some patients owing to painful swollen legs.
      • Ratziu V.
      • Giral P.
      • Jacqueminet S.
      • et al.
      Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial.
      In the PIVENS trial involving patients with NASH randomized to receive pioglitazone, vitamin E, or a placebo for 96 weeks, pioglitazone demonstrated a reduction in hepatic steatosis, lobular inflammation, and hepatic enzymes aspartate aminotransferase (AST) and ALT.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      A meta-analysis evaluated randomized placebo-controlled trials using TZDs in the treatment of patients with NASH. In the identified four high-quality randomized trials, treatment with TZDs resulted in significant decrease in serum ALT along with improvement in steatosis, inflammation, and hepatocyte ballooning, but the change in fibrosis was not statistically significant.
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      But when three studies evaluating the effectiveness of pioglitazone were included, the improvement in fibrosis became statistically significant, suggesting that pioglitazone has superior effects on reversing hepatic fibrosis compared with rosiglitazone.
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      The use of PPARγ agonists is associated with pedal edema, weight gain, cardiac adverse events, and risk of bladder cancer. A recent meta-analysis of 26 studies including 15,332 patients with type 2 diabetes mellitus (T2DM) showed that the odds ratio (OR) for edema with TZDs was 2.26 (95% confidence interval [CI], 2.02–2.53).
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      TZDs are also associated with risk of cardiac adverse events. A meta-analysis of 3 RCTs showed an OR of 2.1, and 4 observation studies showed an OR of 1.55 for heart failure with TZDs.
      • Berlie H.D.
      • Kalus J.S.
      • Jaber L.A.
      Thiazolidinediones and the risk of edema: a meta-analysis.
      Rosiglitazone is associated with more cardiac adverse events than pioglitazone.
      • Singh S.
      • Loke Y.K.
      • Furberg C.D.
      Thiazolidinediones and heart failure: a teleo-analysis.
      The use of pioglitazone was found to be associated with risk of bladder cancer in RCTs (OR, 1.84; 95% CI, 0.99–3.42) and in observational studies (OR, 1.13; 95% CI, 1.03–1.25). The risk of bladder cancer with pioglitazone increased in a dose- and time-dependent manner.
      • Loke Y.K.
      • Kwok C.S.
      • Singh S.
      Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies.
      Table 2 summarizes histology-based studies of PPAR agonists in patients with NAFLD.
      • Fernandez-Miranda C.
      • Perez-Carreras M.
      • Colina F.
      • Lopez-Alonso G.
      • Vargas C.
      • Solis-Herruzo J.A.
      A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease.
      • Laurin J.
      • Lindor K.D.
      • Crippin J.S.
      • et al.
      Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.
      • Deng W.
      • Meng Z.
      • Sun A.
      • Yang Z.
      Pioglitazone suppresses inflammation and fibrosis in nonalcoholic fatty liver disease by down-regulating PDGF and TIMP-2: evidence from in vitro study.
      • Caldwell S.H.
      • Hespenheide E.E.
      • Redick J.A.
      • Iezzoni J.C.
      • Battle E.H.
      • Sheppard B.L.
      A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.
      • Masubuchi Y.
      Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review.
      • Ratziu V.
      • Giral P.
      • Jacqueminet S.
      • et al.
      Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      • Berlie H.D.
      • Kalus J.S.
      • Jaber L.A.
      Thiazolidinediones and the risk of edema: a meta-analysis.
      • Singh S.
      • Loke Y.K.
      • Furberg C.D.
      Thiazolidinediones and heart failure: a teleo-analysis.
      • Loke Y.K.
      • Kwok C.S.
      • Singh S.
      Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies.
      • Tang H.
      • Shi W.
      • Fu S.
      • et al.
      Pioglitazone and bladder cancer risk: a systematic review and meta-analysis.
      • Neuschwander-Tetri B.A.
      • Brunt E.M.
      • Wehmeier K.R.
      • Oliver D.
      • Bacon B.R.
      Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone.
      • Torres D.M.
      • Jones F.J.
      • Shaw J.C.
      • Williams C.D.
      • Ward J.A.
      • Harrison S.A.
      Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial.
      • Belfort R.
      • Harrison S.A.
      • Brown K.
      • et al.
      A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
      • Aithal G.P.
      • Thomas J.A.
      • Kaye P.V.
      • et al.
      Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      • Ratziu V.
      • Harrison S.A.
      • Francque S.
      • et al.
      Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
      Table 2Summary of Studies of PPAR Agonists in NAFLD.
      AuthorN, treatment durationResults
      Biochemical responseHistological response
      Fernandez-Miranda et al
      • Fernandez-Miranda C.
      • Perez-Carreras M.
      • Colina F.
      • Lopez-Alonso G.
      • Vargas C.
      • Solis-Herruzo J.A.
      A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease.
      16, fenofibrate for 48 weeks, no comparative groupSignificant decrease in triglyceride, glucose, liver enzymes, MSDecreased ballooning, grade steatosis, inflammation/fibrosis—no change
      Laurin et al
      • Laurin J.
      • Lindor K.D.
      • Crippin J.S.
      • et al.
      Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.
      16 clofibrate arm, 24 UDCA arm, 1 yearNo change in the clofibrate arm other than decreased ALPNo change in the clofibrate arm
      Neuschwander-Tetri et al
      • Neuschwander-Tetri B.A.
      • Brunt E.M.
      • Wehmeier K.R.
      • Oliver D.
      • Bacon B.R.
      Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone.
      N = 30, 22 had paired biopsies, rosiglitazone for 48 weeks, no comparative groupDecreased AST, ALT, and GGTImproved steatosis and ballooning, weight gain occurred in 67% of patients, and the median weight increase was 7.3%. Within 6 months of completing treatment, liver enzyme levels had increased to near-pretreatment levels
      Ratziu et al
      • Ratziu V.
      • Giral P.
      • Jacqueminet S.
      • et al.
      Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial.
      RCT, 32 rosiglitazone

      31 placebo
      Normalized transaminase levels (38% vs 7%, P = .005)Improved steatosis (47% vs 16%; P = .014), although only half of the patients responded, no change of other histologic parameters, weight gain in rosiglitazone
      Torres et al
      • Torres D.M.
      • Jones F.J.
      • Shaw J.C.
      • Williams C.D.
      • Ward J.A.
      • Harrison S.A.
      Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial.
      RCT, n = 137, rosiglitazone and metformin versus rosiglitazone and losartan versus rosiglitazone alone, 48 weeksDecreased transaminases in all groups108 completed the study, overall improvement of all histologic parameters, no added benefit of metformin (did not prevent weight gain) or losartan
      Belfort et al
      • Belfort R.
      • Harrison S.A.
      • Brown K.
      • et al.
      A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
      RCT, 6 months of low-calorie diet with pioglitazone (n = 26) or diet and placebo (n = 21)Decreased transaminases in pioglitazone armImproved steatosis, inflammation, and ballooning, no change of fibrosis, weight gain despite low-calorie diet in the pioglitazone arm
      Aithal et al
      • Aithal G.P.
      • Thomas J.A.
      • Kaye P.V.
      • et al.
      Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
      RCT, 12 months of diet, exercise, and either placebo or pioglitazone, 30 in placebo and 31 in the pioglitazone arm had paired biopsiesImprovement of ALT and GGTHepatocellular injury (P = .005), Mallory–Denk bodies (P = .004), and fibrosis (P = .05) were reduced in patients treated with pioglitazone, weight gain
      Sanyal et al
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      RCT, pioglitazone (n = 80), vitamin E (n = 83), placebo (n = 84), 96 weeksImprovement of transaminases in the vitamin E and pioglitazone armImprovement in NASH as compared with placebo (vitamin E, P = .001), with (pioglitazone P = .04), both vitamin E and pioglitazone associated with significant reductions in steatosis, lobular inflammation. Improvement in fibrosis, weight gain in pioglitazone
      Cusi et al
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      RCT, 18 months, followed by an 18-month open-label phase with pioglitazone (n = 50) or placebo (n = 51)More normalization in the pioglitazome armPioglitazone is associated with a better NAS reduction and resolution of NASH, steatosis, inflammation, ballooning, no improvement in fibrosis, weight gain
      Ratziu et al
      • Ratziu V.
      • Harrison S.A.
      • Francque S.
      • et al.
      Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
      Elafibranor 120 mg, elafibranor 80 mg, and placeboLiver enzymes, lipids, glucose profiles, and markers of systemic inflammation significantly reduced in the elafibranor 120-mg groupElafibranor 120 mg superior to placebo, NASH resolution without worsening of fibrosis in 19% versus 12% in the placebo group (P = .045), based on a post hoc analysis for the modified definition
      PPAR, peroxisome proliferator-activated receptor; NAFLD, nonalcoholic fatty liver disease; RCT, randomized controlled trial; NASH, nonalcoholic steatohepatitis; NAS, NAFLD activity score; MS, metabolic syndrome; AST, aspartate aminotransferase; ALT, alanine aminotransferase; UDCA, Ursodeoxycholic Acid; GGT, gamma-glutamyl transferase.
      The mitochondrial target of TZD modulators bind and modulate activity of the mitochondrial pyruvate carrier (MPC). MSDC-0602 is the next-generation TZD, which has diminished ability to activate PPARγ.
      • Colca J.R.
      • McDonald W.G.
      • McCommis K.S.
      • Finck B.N.
      Treating fatty liver disease by modulating mitochondrial pyruvate metabolism.
      Improved insulin sensitivity by these compounds decreases lipolysis from adipose tissue and de novo lipogenesis. In addition, blocking pyruvate entry into the mitochondria should normalize the tricarboxylic acid cycle, which is increased in NAFLD. This normalization of the tricarboxylic acid cycle leads to decreased reactive oxygen species and cell damage signals, which should reduce inflammation and stellate cell activation.
      • McCommis K.S.
      • Finck B.N.
      Treating hepatic steatosis and fibrosis by modulating mitochondrial pyruvate metabolism.
      Genetic (selective knockout) or pharmacologic targeting of the MPC by MSDC-0602K has been shown to increase insulin sensitivity and to prevent or reverse NASH pathology in a mouse model.
      • McCommis K.S.
      • Hodges W.T.
      • Brunt E.M.
      • et al.
      Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis.

      Dual and pan-PPAR agonists

      Combining the role of PPARs can result in multiple actions useful to treat NAFLD. If a compound holds desired potency for different PPARs, it can be maximally beneficial with minimal undesired effects. Thus, dual or pan-PPAR agonists can produce antihyperlipidemic (PPARα) effect with insulin sensitization (PPARγ) and increase β-oxidation in the liver and skeletal muscle (α and β/δ) while limiting side effects of singular agonists such as weight gain/cardiac events with TZDs or improving limited clinical efficacy of fibrates. However, development of several agents has been terminated owing to safety concerns, and only few are in later phases of development.
      • Tan C.K.
      • Zhuang Y.
      • Wahli W.
      Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome.
      • a)
        PPARα/δ and their agonists
      In recent years, agonists of PPARs have arisen with affinity for binding to multiple isoforms owing to relatively nonselective ligand-binding pockets, known as dual agonists, and represent interesting therapeutic targets. A novel dual PPARα/δ agonist, GFT505, also known as elafibranor, has been studied in treating NASH. Using various rodent models of NASH, treatment with GFT505 (elafibranor) demonstrated improvement in histologic features of NASH and decreased hepatic triglyceride content, along with reduced expression of inflammatory cytokines and fibrosis markers.
      • Staels B.
      • Rubenstrunk A.
      • Noel B.
      • et al.
      Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      Elafibranor is an agonist of PPARα and PPARδ. Thus, it works on insulin sensitivity, glucose homeostasis, and lipid metabolism. The RCT by Ratziu et al
      • Ratziu V.
      • Harrison S.A.
      • Francque S.
      • et al.
      Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
      (GOLDEN trial) included the following arms: elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), and placebo (n = 92). The study was conducted in Europe and the United States, and the study duration was 52 weeks. The primary outcome was resolution of NASH without worsening of fibrosis. While there was no difference between elafibranor and placebo groups in the primary outcome in intention-to-treat analysis, NASH resolved without worsening of fibrosis in a higher proportion of patients in the 120-mg elafibranor group (19%) versus the placebo group (12%, P = .045), based on a post hoc analysis for the modified definition. The modified definition defined resolution of NASH as disappearance of ballooning with either disappearance of lobular inflammation or persistence of mild inflammation only. Thus, the modified target was pathologic diagnosis of steatosis alone or steatosis with mild inflammation only. The authors found improvement in the histological score after removing patients with mild steatohepatitis from analysis. The outcomes in the 80-mg dose arm were not better than those of placebo. In addition, liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group versus the placebo group. Elafibranor was well tolerated and did not result in weight gain or cardiac events, the authors noted a mild and reversible increase in serum creatinine (4.31 ± 1.19 mmol/L).
      • Ratziu V.
      • Harrison S.A.
      • Francque S.
      • et al.
      Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
      A phase III study (RESOLVE-IT) is presently recruiting a large number of patients with NASH to study the efficacy of elafibranor in comparison with placebo (ClinicalTrials.gov. NCT02704403).
      • b)
        PPARα/γ and their agonists
      Compounds working as PPARα/γ agonists are called glitazars. These compounds improve dyslipidemia, which is α-action, and glycemic parameters/insulin sensitivity, which is γ-action. Thus, theoretically, these compounds address 2 important issues of NAFLD, dyslipidemia and insulin resistance and thus are the area of interest. Several glitazars were initially tried, but their clinical development was stopped later owing to adverse events. Tesaglitazar was the first dual PPARα/γ agonist; a large dose was needed owing to weak action, and clinical development was stopped owing to nephrotoxicity.
      • Hamren B.
      • Ohman K.P.
      • Svensson M.K.
      • Karlsson M.O.
      Pharmacokinetic-pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus.
      Muraglitazar produced better lipid changes, but increase in cardiovascular events was observed.
      • Nissen S.E.
      • Wolski K.
      • Topol E.J.
      Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus.
      • Kendall D.M.
      • Rubin C.J.
      • Mohideen P.
      • et al.
      Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a double-blind, randomized, pioglitazone-comparative study.
      AleCardio was a phase 3 multicenter randomized placebo-controlled trial that was conducted across 26 countries. A total of 7226 patients hospitalized for myocardial infarction or unstable angina with type 2 diabetes received either aleglitazar 150 μg or placebo. The trial was terminated after an interim analysis owing to serious adverse events that included statistically significant gastrointestinal hemorrhages and renal dysfunction in the aleglitazar arm.
      • Lincoff A.M.
      • Tardif J.C.
      • Schwartz G.G.
      • et al.
      Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial.
      Most of these glitazar compounds had significant PPARγ action (than PPARα), which contributes to adverse events. Saroglitazar is the first glitazar class compound approved as a therapeutic agent. Saroglitazar has a different structure from glitazones, other glitazars, and fibrates. It is an aryl alkoxy propionic acid class molecule, which contains a unique pyrol moiety and lacks the glitazone ring. Saroglitazar was designed as a dual PPAR agonist having predominant PPARα effect with moderate PPARγ effect; thus, it provides antilipid effect with insulin sensitization, without being associated with typical glitazone side effects.
      • Krishna Vaseem A.
      • Sah R.K.
      • Ali M.
      Saroglitazar: a novel dual acting peroxisome proliferator activated receptor (PPAR) in dyslipidemia associated with T2DM.
      • Joshi S.R.
      Saroglitazar for the treatment of dyslipidemia in diabetic patients.
      Although the data on the use of saroglitazar in NAFLD are still evolving, based on the results of various studies (PRESSV, VI), Drug Controller General of India has already approved use of saroglitazar for patients with diabetic dyslipidemia, uncontrolled by statins.
      • Agrawal R.
      The first approved agent in the Glitazar's Class: Saroglitazar.
      • Jani R.H.
      • Pai V.
      • Jha P.
      • et al.
      A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI).
      • Pai V.
      • Paneerselvam A.
      • Mukhopadhyay S.
      • et al.
      A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared to pioglitazone 45 mg in diabetic dyslipidemia (PRESS V).
      • Shetty S.R.
      • Kumar S.
      • Mathur R.P.
      • Sharma K.H.
      • Jaiswal A.D.
      Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients.
      In NAFLD, saroglitazar has been shown to be more effective for reduction of the histological NAS than pioglitazone and fenofibrate in a mice model.
      • Jain M.R.
      • Giri S.R.
      • Bhio B.
      • et al.
      Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models.
      C57BL/6 mice that were maintained on choline-deficient, L-amino acid–defined, high-fat diet for 8 weeks were treated with saroglitazar (3 mg/kg), fenofibrate (100 mg/kg), pioglitazone (30 mg/kg), or vehicle for 12 weeks. Saroglitazar reduced hepatic steatosis, inflammation, and ballooning and prevented development of fibrosis. It also reduced serum ALT and AST levels and expression of inflammatory and fibrosis biomarkers. Pioglitazone and fenofibrate did not show any improvement in steatosis but partially improved inflammation and liver function. In the same study, antifibrotic effect of saroglitazar (4 mg/kg) was also observed in the carbon tetrachloride–induced fibrosis model.
      • Jain M.R.
      • Giri S.R.
      • Bhio B.
      • et al.
      Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models.
      Use of saroglitazar in patients with type 2 diabetes mellitus and dyslipidemia or those with type 2 diabetes mellitus and without dyslipidemia has been shown to improve serum transaminase levels.
      • Bhosle D.
      • Bhosle V.
      • Bobde J.
      • Shaikh H.
      • Kadam R.
      Study of saroglitazar in treatment of pre-diabetes with dyslipidemia: STOP-D.
      • Chatterjee S.
      • Majumder A.
      • Ray S.
      Observational study of effects of saroglitazar on glycaemic and lipid parameters on Indian patients with type 2 diabetes.
      A phase II study has also evaluated the improvement in serum ALT levels with saroglitazar in patients with biopsy-proven NASH (CTRI/2010/091/000108).

      ClinicalTrials.gov Identifier: CTRI/2010/091/000108, http://ctri.nic.in/Clinicaltrials/advsearch.php.

      Another phase II study in the USA is evaluating the efficacy of saroglitazar in improving serum liver enzymes and other serum biomarkers of inflammation and fibrosis with improvement in hepatic steatosis on MR imaging-estimated proton density fat fraction (MR-PDFF) in patients with NAFLD/NASH diagnosed on imaging or histology (NCT03061721).

      ClinicalTrials.gov Identifier: NCT03061721 (https://clinicaltrials.gov/ct2/show/NCT03061721).

      In addition, a recent phase III study in India is evaluating the histological efficacy of saroglitazar in comparison with placebo in patients with biopsy-proven NASH (CTRI/2015/10/006236). The results of these studies would clarify the role of saroglitazar in patients with NAFLD.
      • c)
        Pan-PPAR agonists
      Several pan-PPAR agonists are in various phases of development, with many studies reported in animal models.
      • Stienstra R.
      • Mandard S.
      • Patsouris D.
      • Maass C.
      • Kersten S.
      • Muller M.
      Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation.
      • Penna-de-Carvalho A.
      • Graus-Nunes F.
      • Rabelo-Andrade J.
      • Mandarim-de-Lacerda C.A.
      • Souza-Mello V.
      Enhanced pan-peroxisome proliferator-activated receptor gene and protein expression in adipose tissue of diet-induced obese mice treated with telmisartan.
      • Sadasivuni M.K.
      • Reddy B.M.
      • Singh J.
      • et al.
      CNX-013-B2, a unique pan tissue acting rexinoid, modulates several nuclear receptors and controls multiple risk factors of the metabolic syndrome without risk of hypertriglyceridemia, hepatomegaly and body weight gain in animal models.
      • Chen W.
      • Fan S.
      • Xie X.
      • Xue N.
      • Jin X.
      • Wang L.
      Novel PPAR pan agonist, ZBH ameliorates hyperlipidemia and insulin resistance in high fat diet induced hyperlipidemic hamster.
      • Harrington W.W.
      • S Britt C.
      • G Wilson J.
      • et al.
      The effect of PPARalpha, PPARdelta, PPARgamma, and PPARpan agonists on body weight, body mass, and serum lipid profiles in diet-induced obese AKR/J mice.
      • Feng L.
      • Luo H.
      • Xu Z.
      • et al.
      Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-gamma and PPAR-alpha agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice.
      Bezafibrate has predominantly alpha action and has been shown to improve glycated hemoglobin in patients with diabetes mellitus.
      • Tenenbaum A.
      • Fisman E.Z.
      Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?.
      • Ogawa S.
      • Takeuchi K.
      • Sugimura K.
      • et al.
      Bezafibrate reduces blood glucose in type 2 diabetes mellitus.
      Bezafibrate has also been shown to improve atherogenic dyslipidemia and insulin resistance without causing overweight.
      • Tenenbaum A.
      • Fisman E.Z.
      Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?.
      • Ogawa S.
      • Takeuchi K.
      • Sugimura K.
      • et al.
      Bezafibrate reduces blood glucose in type 2 diabetes mellitus.
      • The BIP Study Group
      Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.
      Although human studies are lacking, bezafibrate has been shown to improve NAFLD and diabetes in mice models.
      • Franko A.
      • Neschen S.
      • Rozman J.
      • et al.
      Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice.
      • Sasaki Y.
      • Shimada T.
      • Iizuka S.
      • et al.
      Effects of bezafibrate in nonalcoholic steatohepatitis model mice with monosodium glutamate-induced metabolic syndrome.
      Lanifibranor (IV1337) is another pan-PPAR agonist, which in addition to improving insulin sensitivity, has been shown to have antilipid, anti-inflammatory, and antifibrosis properties.
      • Ruzehaji N.
      • Frantz C.
      • Ponsoye M.
      • et al.
      Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis.
      • Avouac J.
      • Konstantinova I.
      • Guignabert C.
      • et al.
      Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension.
      • Wettstein G.
      • Luccarini J.M.
      • Poekes L.
      • et al.
      The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis.
      In animal models, lanifibranor has been shown to improve insulin sensitivity and decrease hepatic steatosis, inflammation, ballooning, and fibrosis in liver tissue.
      • Ruzehaji N.
      • Frantz C.
      • Ponsoye M.
      • et al.
      Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis.
      An ongoing study is evaluating the efficacy of lanifibranor in patients with diabetes and NAFLD (ClinicalTrials.gov: NCT03459079).
      PPAR agonists are attractive targets for the treatment of patients with NAFLD, given multiple actions of the PPAR on lipid metabolism, oxidation of FAs, glucose homeostasis, and inflammation. This becomes all the more important in absence of any recommended pharmacotherapy for these patients. Of all the PPAR agonists, the PPARγ agonist pioglitazone is the most extensively evaluated and has been found to be useful in patients with NAFLD but is limited by its side effect profile. Emerging data of dual PPAR agonists and pan-PPAR agonists appear encouraging and may hold promise for patients with NAFLD.

      Conflicts of interest

      The authors have none to declare.

      References

        • Ahmed W.
        • Ziouzenkova O.
        • Brown J.
        • et al.
        PPARs and their metabolic modulation: new mechanisms for transcriptional regulation?.
        J Intern Med. 2007; 262: 184-198
        • Poulsen L.
        • Siersbaek M.
        • Mandrup S.
        PPARs: fatty acid sensors controlling metabolism.
        Semin Cell Dev Biol. 2012; 23: 631-639
        • Grygiel-Górniak B.
        Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review.
        Nutr J. 2014 14; 13: 17
        • Pawlak M.
        • Lefebvre P.
        • Staels B.
        Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease.
        J Hepatol. 2015; 62: 720-733
        • Tailleux A.
        • Wouters K.
        • Staels B.
        Roles of PPARs in NAFLD: potential therapeutic targets.
        Biochim Biophys Acta. 2012; 1821: 809-818
        • Corton J.C.
        Evaluation of the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver tumor induction by trichloroethylene and metabolites.
        Crit Rev Toxicol. 2008; 38: 857-875
        • Fisher C.D.
        • Jackson J.P.
        • Lickteig A.J.
        • Augustine L.M.
        • Cherrington N.J.
        Drug metabolizing enzyme induction pathways in experimental non-alcoholic steatohepatitis.
        Arch Toxicol. 2008; 82: 959-964
        • Takeuchi S.
        • Matsuda T.
        • Kobayashi S.
        • Takahashi T.
        • Kojima H.
        In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma and quantitative analysis of in vivo induction pathway.
        Toxicol Appl Pharmacol. 2006; 217: 235-244
        • Laughter A.R.
        • Dunn C.S.
        • Swanson C.L.
        • Howroyd P.
        • Cattley R.C.
        • Corton J.C.
        Role of the peroxisome proliferator-activated receptor alpha (PPARalpha) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver.
        Toxicology. 2004; 203: 83-98
        • Evans R.M.
        • Barish G.D.
        • Wang Y.X.
        PPARs and the complex journey to obesity.
        Nat Med. 2004; 10: 355-361
        • Desvergne B.
        • Wahli W.
        Peroxisome proliferator-activated receptors: nuclear control of metabolism.
        Endocr Rev. 1999; 20: 649-688
        • Issemann I.
        • Green S.
        Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.
        Nature. 1990; 347: 645-650
        • Duseja A.
        • Najmy S.
        • Sachdev S.
        • et al.
        High prevalence of non-alcoholic fatty liver disease among healthy male blood donors of urban India.
        JGH Open. 2019; 3: 133-139
        • Duseja A.
        • Sharma B.
        • Kumar A.
        • et al.
        Nonalcoholic fatty liver in a developing country is responsible for significant liver disease.
        Hepatology. 2010; 52: 2248-2249
        • Duseja A.
        • Singh S.P.
        • Saraswat V.A.
        • et al.
        Non-alcoholic fatty liver disease and metabolic syndrome-position paper of the Indian national association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology.
        J. Clin. Exp. Hepatol. 2015; 5: 51-68
        • Tyagi S.
        • Gupta P.
        • Saini A.S.
        • Kaushal C.
        • Sharma S.
        The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases.
        "J Adv Pharm Technol Research"" (JAPTR)". 2011; 2: 236-240
        • Lefebvre P.
        • Chinetti G.
        • Fruchart J.C.
        • Staels B.
        Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis.
        J Clin Investig. 2006; 116: 571-580
        • Vanden Berghe W.
        • Vermeulen L.
        • Delerive P.
        • De Bosscher K.
        • Staels B.
        • Haegeman G.
        A paradigm for gene regulation: inflammation, NF-kappaB and PPAR.
        Adv Exp Med Biol. 2003; 544: 181-196
        • Delerive P.
        • Gervois P.
        • Fruchart J.C.
        • Staels B.
        Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators.
        J Biol Chem. 2000; 275: 36703-36707
        • Serviddio G.
        • Giudetti A.M.
        • Bellanti F.
        • et al.
        Oxidation of hepatic carnitine palmitoyl transferase-I (CPT-I) impairs fatty acid beta-oxidation in rats fed a methionine-choline deficient diet.
        PLoS One. 2011; 6: e24084
        • Yu G.S.
        • Lu Y.C.
        • Gulick T.
        Co-regulation of tissue-specific alternative human carnitine palmitoyltransferase Ibeta gene promoters by fatty acid enzyme substrate.
        J Biol Chem. 1998; 273: 32901-32909
        • Brandt J.M.
        • Djouadi F.
        • Kelly D.P.
        Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha.
        J Biol Chem. 1998; 273: 23786-23792
        • Hashimoto T.
        • Cook W.S.
        • Qi C.
        • Yeldandi A.V.
        • Reddy J.K.
        • Rao M.S.
        Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting.
        J Biol Chem. 2000; 275: 28918-28928
        • Fraulob J.C.
        • Souza-Mello V.
        • Aguila M.B.
        • Mandarim-de-Lacerda C.A.
        Beneficial effects of rosuvastatin on insulin resistance, adiposity, inflammatory markers and non-alcoholic fatty liver disease in mice fed on a high-fat diet.
        Clin Sci. 2012; 123: 259-270
        • Souza-Mello V.
        • Gregorio B.M.
        • Cardoso-de-Lemos F.S.
        • de Carvalho L.
        • Aguila M.B.
        • Mandarim-de-Lacerda C.A.
        Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet.
        Clin Sci (Lond). 2010; 119: 239-250
        • Stienstra R.
        • Mandard S.
        • Patsouris D.
        • Maass C.
        • Kersten S.
        • Muller M.
        Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation.
        Endocrinology. 2007; 148: 2753-2763
        • Patsouris D.
        • Reddy J.K.
        • Muller M.
        • Kersten S.
        Peroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression.
        Endocrinology. 2006; 147: 1508-1516
        • Abdelmegeed M.A.
        • Yoo S.H.
        • Henderson L.E.
        • Gonzalez F.J.
        • Woodcroft K.J.
        • Song B.J.
        PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver.
        J Nutr. 2011; 141: 603-610
        • Tan C.K.
        • Zhuang Y.
        • Wahli W.
        Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome.
        Expert Opin Ther Targets. 2017; 21: 333-348
        • Ip E.
        • Farrell G.C.
        • Robertson G.
        • Hall P.
        • Kirsch R.
        • Leclercq I.
        Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice.
        Hepatology. 2003; 38: 123-132
        • Fernandez-Miranda C.
        • Perez-Carreras M.
        • Colina F.
        • Lopez-Alonso G.
        • Vargas C.
        • Solis-Herruzo J.A.
        A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease.
        Dig Liver Dis. 2008; 40: 200-205
        • Basaranoglu M.
        • Acbay O.
        • Sonsuz A.
        A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis.
        J Hepatol. 1999; 31: 384
        • El-Haggar S.M.
        • Mostafa T.M.
        Comparative clinical study between the effect of fenofibrate alone and its combination with pentoxifylline on biochemical parameters and liver stiffness in patients with non-alcoholic fatty liver disease.
        Hepatol Int. 2015; 9: 471-479
        • Laurin J.
        • Lindor K.D.
        • Crippin J.S.
        • et al.
        Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.
        Hepatology. 1996; 23: 1464-1467
        • Ishibashi S.
        • Yamashita S.
        • Arai H.
        • et al.
        Effects of K-877, a novel selective PPARalpha modulator (SPPARMalpha), in dyslipidaemic patients: a randomized, double blind, active- and placebo-controlled, phase 2 trial.
        Atherosclerosis. 2016; 249: 36-43
        • Araujo S.
        • Soares E.S.A.
        • Gomes F.
        • et al.
        Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease (NAFLD).
        Eur J Pharmacol. 2016; 788: 306-314
        • Gross B.
        • Staels B.
        PPAR agonists: multimodal drugs for the treatment of type-2 diabetes.
        Best Pract Res Clin Endocrinol Metabol. 2007; 21: 687-710
        • Odegaard J.I.
        • Ricardo-Gonzalez R.R.
        • Goforth M.H.
        • et al.
        Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.
        Nature. 2007; 447: 1116-1120
        • Tanaka T.
        • Yamamoto J.
        • Iwasaki S.
        • et al.
        Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome.
        Proc Natl Acad Sci U S A. 2003; 100: 15924-15929
        • Riserus U.
        • Sprecher D.
        • Johnson T.
        • et al.
        Activation of peroxisome proliferator-activated receptor (PPAR) delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men.
        Diabetes. 2008; 57: 332-339
        • Peters J.M.
        • Gonzalez F.J.
        • Muller R.
        Establishing the role of PPARbeta/delta in carcinogenesis.
        Trends Endocrinol Metabol. 2015; 26: 595-607
        • Lee M.Y.
        • Choi R.
        • Kim H.M.
        • et al.
        Peroxisome proliferator-activated receptor δ agonist attenuates hepatic steatosis by anti-inflammatory mechanism.
        Exp Mol Med. 2012; 44: 578-585
        • Shan W.
        • Palkar P.S.
        • Murray I.A.
        • et al.
        Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression.
        Toxicol Sci. 2008; 105: 418-428
        • Bays H.E.
        • Schwartz S.
        • Littlejohn 3rd, T.
        • et al.
        MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin.
        J Clin Endocrinol Metab. 2011; 96: 2889-2897
        • Haczeyni F.
        • Wang H.
        • Barn V.
        • et al.
        The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice.
        Hepatol Commun. 2017; 1: 663-674
        • Zhu Y.
        • Alvares K.
        • Huang Q.
        • Rao M.S.
        • Reddy J.K.
        Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver.
        J Biol Chem. 1993; 268: 26817-26820
        • Zhong X.
        • Liu H.
        Honokiol attenuates diet-induced non-alcoholic steatohepatitis by regulating macrophage polarization through activating peroxisome proliferator-activated receptor gamma.
        J Gastroenterol Hepatol. 2018; 33: 524-532
        • Yki-Jarvinen H.
        Thiazolidinediones.
        N Engl J Med. 2004; 351: 1106-1118
        • Nan Y.M.
        • Fu N.
        • Wu W.J.
        • et al.
        Rosiglitazone prevents nutritional fibrosis and steatohepatitis in mice.
        Scand J Gastroenterol. 2009; 44: 358-365
        • Deng W.
        • Meng Z.
        • Sun A.
        • Yang Z.
        Pioglitazone suppresses inflammation and fibrosis in nonalcoholic fatty liver disease by down-regulating PDGF and TIMP-2: evidence from in vitro study.
        Cancer Biomark. 2017; 20: 411-415
        • Caldwell S.H.
        • Hespenheide E.E.
        • Redick J.A.
        • Iezzoni J.C.
        • Battle E.H.
        • Sheppard B.L.
        A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.
        Am J Gastroenterol. 2001; 96: 519-525
        • Masubuchi Y.
        Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review.
        Drug Metab Pharmacokinet. 2006; 21: 347-356
        • Ratziu V.
        • Giral P.
        • Jacqueminet S.
        • et al.
        Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial.
        Gastroenterology. 2008; 135: 100-110
        • Sanyal A.J.
        • Chalasani N.
        • Kowdley K.V.
        • et al.
        Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
        N Engl J Med. 2010; 362: 1675-1685
        • Boettcher E.
        • Csako G.
        • Pucino F.
        • Wesley R.
        • Loomba R.
        Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
        Aliment Pharmacol Ther. 2012; 35: 66-75
        • Berlie H.D.
        • Kalus J.S.
        • Jaber L.A.
        Thiazolidinediones and the risk of edema: a meta-analysis.
        Diabetes Res Clin Pract. 2007; 76: 279-289
        • Singh S.
        • Loke Y.K.
        • Furberg C.D.
        Thiazolidinediones and heart failure: a teleo-analysis.
        Diabetes Care. 2007; 30: 2148-2153
        • Loke Y.K.
        • Kwok C.S.
        • Singh S.
        Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies.
        BMJ. 2011; 342: d1309
        • Tang H.
        • Shi W.
        • Fu S.
        • et al.
        Pioglitazone and bladder cancer risk: a systematic review and meta-analysis.
        Cancer Med. 2018; 7: 1070-1080
        • Neuschwander-Tetri B.A.
        • Brunt E.M.
        • Wehmeier K.R.
        • Oliver D.
        • Bacon B.R.
        Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone.
        Hepatology. 2003; 38: 1008-1017
        • Torres D.M.
        • Jones F.J.
        • Shaw J.C.
        • Williams C.D.
        • Ward J.A.
        • Harrison S.A.
        Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial.
        Hepatology. 2011; 54: 1631-1639
        • Belfort R.
        • Harrison S.A.
        • Brown K.
        • et al.
        A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
        N Engl J Med. 2006; 355: 2297-2307
        • Aithal G.P.
        • Thomas J.A.
        • Kaye P.V.
        • et al.
        Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
        Gastroenterology. 2008; 135: 1176-1184
        • Cusi K.
        • Orsak B.
        • Bril F.
        • et al.
        Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
        Ann Intern Med. 2016; 165: 305-315
        • Colca J.R.
        • McDonald W.G.
        • McCommis K.S.
        • Finck B.N.
        Treating fatty liver disease by modulating mitochondrial pyruvate metabolism.
        Hepatol Commun. 2017; 1: 193-197
        • McCommis K.S.
        • Finck B.N.
        Treating hepatic steatosis and fibrosis by modulating mitochondrial pyruvate metabolism.
        Cell Mol Gastroenterol Hepatol. 2019; 7: 275-284
        • McCommis K.S.
        • Hodges W.T.
        • Brunt E.M.
        • et al.
        Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis.
        Hepatology. 2017; 65: 1543-1556
        • Ratziu V.
        • Harrison S.A.
        • Francque S.
        • et al.
        Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.
        Gastroenterology. 2016; 150 (e5): 1147-1159
        • Staels B.
        • Rubenstrunk A.
        • Noel B.
        • et al.
        Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
        Hepatology. 2013; 58: 1941-1952
        • Hamren B.
        • Ohman K.P.
        • Svensson M.K.
        • Karlsson M.O.
        Pharmacokinetic-pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus.
        J Clin Pharmacol. 2012; 52: 1317-1327
        • Nissen S.E.
        • Wolski K.
        • Topol E.J.
        Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus.
        J Am Med Assoc. 2005; 294: 2581-2586
        • Kendall D.M.
        • Rubin C.J.
        • Mohideen P.
        • et al.
        Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a double-blind, randomized, pioglitazone-comparative study.
        Diabetes Care. 2006; 29: 1016-1023
        • Lincoff A.M.
        • Tardif J.C.
        • Schwartz G.G.
        • et al.
        Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial.
        J Am Med Assoc. 2014; 16: 1515-1525
        • Krishna Vaseem A.
        • Sah R.K.
        • Ali M.
        Saroglitazar: a novel dual acting peroxisome proliferator activated receptor (PPAR) in dyslipidemia associated with T2DM.
        Ejpmr. 2017; 4: 680-684
        • Joshi S.R.
        Saroglitazar for the treatment of dyslipidemia in diabetic patients.
        Expert Opin Pharmacother. 2015; 16: 597-606
        • Agrawal R.
        The first approved agent in the Glitazar's Class: Saroglitazar.
        Curr Drug Targets. 2014; 15: 151-155
        • Jani R.H.
        • Pai V.
        • Jha P.
        • et al.
        A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI).
        Diabetes Technol Ther. 2014; 16: 63-71
        • Pai V.
        • Paneerselvam A.
        • Mukhopadhyay S.
        • et al.
        A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared to pioglitazone 45 mg in diabetic dyslipidemia (PRESS V).
        J Diabetes Sci Technol. 2014; 8: 132-141
        • Shetty S.R.
        • Kumar S.
        • Mathur R.P.
        • Sharma K.H.
        • Jaiswal A.D.
        Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients.
        Indian Heart J. 2015; 67: 23-26
        • Jain M.R.
        • Giri S.R.
        • Bhio B.
        • et al.
        Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models.
        Liver Int. 2018; 38: 1084-1094
        • Bhosle D.
        • Bhosle V.
        • Bobde J.
        • Shaikh H.
        • Kadam R.
        Study of saroglitazar in treatment of pre-diabetes with dyslipidemia: STOP-D.
        J Assoc Phys India. 2018; 66: 14-17
        • Chatterjee S.
        • Majumder A.
        • Ray S.
        Observational study of effects of saroglitazar on glycaemic and lipid parameters on Indian patients with type 2 diabetes.
        Sci Rep. 2015; 5: 7706
      1. ClinicalTrials.gov Identifier: CTRI/2010/091/000108, http://ctri.nic.in/Clinicaltrials/advsearch.php.

      2. ClinicalTrials.gov Identifier: NCT03061721 (https://clinicaltrials.gov/ct2/show/NCT03061721).

      3. CTRI/2015/10/006236,http://ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=11280&EncHid=&modid=&compid=%27,%2711280det%27.

        • Penna-de-Carvalho A.
        • Graus-Nunes F.
        • Rabelo-Andrade J.
        • Mandarim-de-Lacerda C.A.
        • Souza-Mello V.
        Enhanced pan-peroxisome proliferator-activated receptor gene and protein expression in adipose tissue of diet-induced obese mice treated with telmisartan.
        Exp Physiol. 2014; 99: 1663-1678
        • Sadasivuni M.K.
        • Reddy B.M.
        • Singh J.
        • et al.
        CNX-013-B2, a unique pan tissue acting rexinoid, modulates several nuclear receptors and controls multiple risk factors of the metabolic syndrome without risk of hypertriglyceridemia, hepatomegaly and body weight gain in animal models.
        Diabetol Metab Syndrome. 2014; 6: 83
        • Chen W.
        • Fan S.
        • Xie X.
        • Xue N.
        • Jin X.
        • Wang L.
        Novel PPAR pan agonist, ZBH ameliorates hyperlipidemia and insulin resistance in high fat diet induced hyperlipidemic hamster.
        PLoS One. 2014; 9: e96056
        • Harrington W.W.
        • S Britt C.
        • G Wilson J.
        • et al.
        The effect of PPARalpha, PPARdelta, PPARgamma, and PPARpan agonists on body weight, body mass, and serum lipid profiles in diet-induced obese AKR/J mice.
        PPAR Res. 2007; 2007: 97125
        • Feng L.
        • Luo H.
        • Xu Z.
        • et al.
        Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-gamma and PPAR-alpha agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice.
        Diabetologia. 2016; 59: 1276-1286
        • Tenenbaum A.
        • Fisman E.Z.
        Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?.
        Cardiovasc Diabetol. 2012; 11: 140
        • Ogawa S.
        • Takeuchi K.
        • Sugimura K.
        • et al.
        Bezafibrate reduces blood glucose in type 2 diabetes mellitus.
        Metabolism. 2000; 49: 331-334
        • The BIP Study Group
        Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.
        Circulation. 2000; 102: 21-27
        • Franko A.
        • Neschen S.
        • Rozman J.
        • et al.
        Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice.
        Mol Metab. 2017; 6: 256-266
        • Sasaki Y.
        • Shimada T.
        • Iizuka S.
        • et al.
        Effects of bezafibrate in nonalcoholic steatohepatitis model mice with monosodium glutamate-induced metabolic syndrome.
        Eur J Pharmacol. 2011; 662: 1-8
        • Ruzehaji N.
        • Frantz C.
        • Ponsoye M.
        • et al.
        Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis.
        Ann Rheum Dis. 2016; 75: 2175-2183
        • Avouac J.
        • Konstantinova I.
        • Guignabert C.
        • et al.
        Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension.
        Ann Rheum Dis. 2017; 76: 1931-1940
        • Wettstein G.
        • Luccarini J.M.
        • Poekes L.
        • et al.
        The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis.
        Hepatol Commun. 2017; 1: 524-537