Dual <scp>PPAR</scp>α/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental <scp>NASH</scp> models

Jain, Mukul; Giri, Suresh; Bhoi, Bibhuti; Trivedi, Chitrang; Rath, Akshyaya; Rathod, Rohan; Ranvir, Ramchandra; Kadam, Shekhar; Patel, Hiren; Swain, Prabodha; Roy, Sib Sankar; Das, Nandini; Karmakar, Eshani; Wahli, Walter; Patel, Pankaj

doi:10.1111/liv.13634

Cited by 162 publications

(119 citation statements)

References 29 publications

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“…Glitazars constitute a novel group of dual agonists targeting both PPARγ and PPARα . Of these, saroglitazar has shown promising results in pre‐clinical models, reversing CCL 4 ‐induced hepatic fibrosis and NASH caused by a CDAA diet in mice . Specifically, saroglitazar improved steatosis, hepatocellular ballooning, lobular inflammation and fibrosis (scored collectively) by 78% whereas pioglitazone showed 22% and fenofibrate (a PPARα agonist) a 54% improvement, all compared with vehicle .…”

Section: Emerging Strategies To Target Pparγ In the Treatment Of Nafldmentioning

confidence: 99%

“…Of these, saroglitazar has shown promising results in pre‐clinical models, reversing CCL 4 ‐induced hepatic fibrosis and NASH caused by a CDAA diet in mice . Specifically, saroglitazar improved steatosis, hepatocellular ballooning, lobular inflammation and fibrosis (scored collectively) by 78% whereas pioglitazone showed 22% and fenofibrate (a PPARα agonist) a 54% improvement, all compared with vehicle . Saroglitazar is currently approved for the treatment of diabetic hypertriglyceridaemia and dyslipidaemia in India, and a phase 3 clinical trial comparing saroglitazar and pioglitazone treatment in NAFLD patients is currently ongoing (ClinicalTrials.gov identifier: NCT02265276).…”

Section: Emerging Strategies To Target Pparγ In the Treatment Of Nafldmentioning

confidence: 99%

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A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Skat-Rørdam

Ipsen

Lykkesfeldt

et al. 2019

Basic Clin Pharma Tox

136

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Non-alcoholic fatty liver disease is becoming a major health burden, as prevalence increases and there are no approved treatment options. Thiazolidinediones target the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) and have been investigated in several clinical trials for their potential in treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). PPARγ has specialized roles in distinct tissues and cell types, and although the primary function of PPARγ is in adipose tissue, where the highest expression levels are observed, hepatic expression levels of PPARγ are significantly increased in patients with NAFLD. Thus, NAFLD patients receiving treatment with PPARγ agonists might have a liver response apart from the one in adipose tissue. Owing to the different roles of PPARγ, new treatment strategies include development of compounds harnessing the beneficial effects of PPARγ while restricting PPARγ unwanted effects such as adipogenesis resulting in weight gain. Furthermore, dual or pan agonists targeting two or more of the PPARs have shown promising results in pre-clinical research and some are currently proceeding to clinical trials. This MiniReview explores adipose-and liver-specific actions of PPARγ, and how this knowledge may contribute in the search for new treatment modalities in NAFLD/NASH.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Section: Emerging Strategies To Target Pparγ In the Treatment Of Nafldmentioning

confidence: 99%

Section: Emerging Strategies To Target Pparγ In the Treatment Of Nafldmentioning

confidence: 99%

A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Skat-Rørdam

Ipsen

Lykkesfeldt

et al. 2019

Basic Clin Pharma Tox

136

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“…Saroglitazar, which is already authorized in India for the treatment of diabetic dyslipidemia [70], has predominant PPAR-α activity but also agonizes PPAR-γ. This compound induced a reduction of NASH characteristics in both in vitro (palmitate-exposed HepG2 and HepG2-LX2 co-cultures) and in vivo (choline-deficient HFD-fed mice) models, where it seemed to be more effective than pioglitazone and fenofibrate [71]. Saroglitazar is currently being evaluated in a clinical phase II study (Table 1), but no clinical results have been divulgated.…”

Section: Ppar-α/γ Agonistsmentioning

confidence: 99%

“…Hitherto, elafibranor, currently being evaluated in a clinical phase III trial, seems to pose the best outbalanced activity on the PPAR-α and -δ isotypes to treat NASH [67]. Nonetheless, two other PPAR agonists, lanifibranor [74] and saroglitazar [71], respectively a PPAR-pan and PPAR-α/γ agonist, are both being tested in clinical phase II trials and seem promising as well.…”

Section: Outlook and Conclusionmentioning

confidence: 99%

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

Boeckmans

Natale

Rombaut

et al. 2019

Cells

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Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.

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“…Although many of these drugs are not yet available on the market, some have shown great promise, and their efficacies are being evaluated via ongoing clinical trials such as Evidences IV (saroglitazar; Zydus Cadila, Ahmedabad, India) (https://clinicaltrials.gov/ identifier: NCT03061721) and Resolve-it (elafibranor, GFT505; Genfit, Loos, France) (https://clinicaltrials.gov/ identifier: NCT02704403) (110). Elafibranor and saroglitazar are dual-PPAR agonists that have been shown to improve NASH, with favorable outcomes such as better cardiometabolic profile, lower lipid levels, and better insulin sensitivity (111)(112)(113). Saroglitazar (trade name Lipaglyn) is approved for use in India by the Drug Controller General of India to treat diabetic dyslipidemia and hypertriglyceridemia with type 2 diabetes not controlled by statin therapy.…”

Section: Pparsmentioning

confidence: 99%

The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology

Visvalingam

Wahli

2019

FASEB j.

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The human gut is colonized by commensal microorganisms, predominately bacteria that have coevolved in symbiosis with their host. The gut microbiota has been extensively studied in recent years, and many important findings on how it can regulate host metabolism have been unraveled. In healthy individuals, feeding timing and type of food can influence not only the composition but also the circadian oscillation of the gut microbiota. Host feeding habits thus influence the type of microbe‐derived metabolites produced and their concentrations throughout the day. These microbe‐derived metabolites influence many aspects of host physiology, including energy metabolism and circadian rhythm. Peroxisome proliferator‐activated receptors (PPARs) are a group of ligand‐activated transcription factors that regulate various metabolic processes such as fatty acid metabolism. Similar to the gut microbiota, PPAR expression in various organs oscillates diurnally, and studies have shown that the gut microbiota can influence PPAR activities in various metabolic organs. For example, short‐chain fatty acids, the most abundant type of metabolites produced by anaerobic fermentation of dietary fibers by the gut microbiota, are PPAR agonists. In this review, we highlight how the gut microbiota can regulate PPARs in key metabolic organs, namely, in the intestines, liver, and muscle. Knowing that the gut microbiota impacts metabolism and is altered in individuals with metabolic diseases might allow treatment of these patients using noninvasive procedures such as gut microbiota manipulation.—Oh, H. Y. P., Visvalingam, V., Wahli, W. The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology. FASEB J. 33, 9706–9730 (2019). http://www.fasebj.org

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Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models

Cited by 162 publications

References 29 publications

A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Anti-NASH Drug Development Hitches a Lift on PPAR Agonism

The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology

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