The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease

Abstract

Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would improve nASH in the diet-induced animal model of nAfLD. Mice received chow diet and normal water (CDNW) or high fat western diet and ad lib sugar water (WDSW). After 12 weeks, WDSW fed mice were randomized to receive (1) WDSW alone, (2) WDSW + vehicle, (3) WDSW + pioglitazone or (4) WDSW + saroglitazar for an additional 12 weeks. Compared to mice on WDSW and vehicle controls, mice receiving WDSW + saroglitazar had lower weight, lower HOMA-IR, triglycerides, total cholesterol, and ALT. Saroglitazar improved steatosis, lobular inflammation, hepatocellular ballooning and fibrosis stage. NASH resolved in all mice receiving saroglitazar. These effects were at par with or superior to pioglitazone. Molecular analyses confirmed target engagement and reduced oxidative stress, unfolded protein response and fibrogenic signaling. Transcriptomic analysis further confirmed increased PPARtarget expression and an anti-inflammatory effect with saroglitazar. Lipidomic analyses demonstrated that saroglitazar also reduced triglycerides, diglycerides, sphingomyelins and ceramides. These preclinical data provide a strong rationale for developing saroglitazar for the treatment of nASH in humans. Nonalcoholic fatty liver disease (NAFLD) encompasses a continuum of liver disease ranging from fatty liver (NAFL) to steatohepatitis (NASH), fibrosis and cirrhosis 1-3. This rising prevalence of NASH is accompanied with an alarming increase in the number of patients with cirrhosis and hepatocellular carcinoma (HCC) necessitating liver transplantation 4,5. Dynamic models of disease progression predict a doubling of the burden of end-stage liver disease from the NAFLD epidemic by 2030 if left unmanaged 6. Despite progress in understanding the clinical drivers of disease progression and pathogenesis of NAFLD and an exponential increase in clinical trials investigating the therapeutic potential and identifying therapeutic targets, there are immediate unmet medical needs and challenges and the disease still remains without any approved drugs 7,8. A key consideration in therapeutic development for NASH is the identification of a rational therapeutic target. NASH often develops in the context of excess adiposity and systemic insulin resistance 9. The current paradigm for the pathogenesis of NASH starts with increased delivery of lipids such as free fatty acids (FFA), carbohydrates along with inflammatory cytokines and gut-microbiome-derived products e.g. endotoxin 10 .

Effectiveness of The PPAR Agonist Saroglitazar in Nonalcoholic Steatohepatitis: Positive Data from Preclinical & Clinical Studies

“…4 Pioglitazone reduced mean SAF activity to 2 (± 0.6) and mean NAS to 4.9 (± 0.7). 4 Saroglitazar signi cantly reduced steatosis, lobular in ammation, and hepatocellular ballooning (p < 0.01). 4 In the Saroglitazar treated group, hepatocellular ballooning was absent in all mice, steatohepatitis was resolved in all the mice, 3 out of 12 mice had no histological evidence of NAFLD.…”

“…4 Saroglitazar decreased TNF-α and increased circulating adiponectin compared to WDSW vehicle control. 4 Diet-induced obesity and insulin resistance:…”

“…4 Saroglitazar signi cantly reduced steatosis, lobular in ammation, and hepatocellular ballooning (p < 0.01). 4 In the Saroglitazar treated group, hepatocellular ballooning was absent in all mice, steatohepatitis was resolved in all the mice, 3 out of 12 mice had no histological evidence of NAFLD. 4 Saroglitazar reduced mean NAS to 1.45 (± 0.9), which was signi cantly lower than that in the WDSW vehicle group.…”

“…2,3 NASH mainly develops due to excess adiposity and systemic insulin resistance. 4 The pathogenesis of NASH initiates with increased delivery of free fatty acids (FFA), carbohydrates, in ammatory cytokines and gut-microbiome-derived products such as endotoxin to the liver. 4 This leads to an overloading of the hepatocellular metabolic machinery, which results in accumulation of lipids (mainly triglycerides) and induces cell stress that can trigger in ammatory and apoptotic signaling.…”

“…We believe that such a comprehensive discussion of the pre-clinical e cacy and the clinical e cacy in the same article, in which the effect on the typical pathological features of NASH can be correlated and understood, will provide the scienti c community a comprehensive and holistic understanding of the effect of Saroglitazar in NASH. 4,9,10 All the data depicted and discussed in this article are 'data on le'. The pre-clinical DIAMOND mice model study results have been published in Scienti c Reports (a nature research journal) 4 / presented at the Liver Meeting 2018, AASLD, the USA (Abstract # 1297(Abstract # , 1768(Abstract # , and 1795.…”