PPAR-delta Agonist MBX-8025 Abolishes Lipotoxicity andReverses NASH in Diabetic Obese Mice

Abstract

Background: Lipotoxicity associated with insulin resistance and diabetes is central to the pathogenesis of non-alcoholic steatohepatitis (NASH), and resultant liver fibrosis and cirrhosis. To date, only weight loss, which improves insulin sensitivity, reverses NASH fibrosis; pharmacological agents have limited efficacy. The mixed peroxisome proliferator-activated receptor-alpha/delta (PPAR-α/δ) agonist, GFT505, has demonstrated some efficacy in NASH. MBX-8025 is a selective PPAR-δ agonist that improves atherogenic dyslipidemia in rodents and humans. We tested whether MBX-8025 could reverse lipotoxicity and NASH in a diabetic mouse model. Methods: From 4 weeks of age, female Alms1 mutant (foz/ foz) and wildtype (Wt) mice were fed an atherogenic diet for 16 weeks, after which groups (8-12 mice) were randomized to receive MBX-8025 (10mg/kg) or vehicle (1% methylcellulose) by gavage for 8 weeks. We performed intraperitoneal glucose tolerance testing (IpGTT) at Week 27, and sacrifice at 28 weeks. Results: MBX-8025 had minimal effect on body or liver weight, but normalized hyperglycemia, hypercholesterolaemia, hyperinsulinemia and glucose disposal (by IpGTT) in foz/foz mice. After 16 weeks of atherogenic dietary intake, serum ALT ranged from 300-600 U/L in vehicle-treated foz/ foz mice; MBX-8025 reduced this by ~50% (P<0.05). In foz/ foz mice, hepatic lipid fractions showed increased free cholesterol, diacylglycerol, saturated fatty acid and triglyceride content. MBX-8025 normalized serum lipids, and corrected all hepatic lipid pools. This was associated with abolition of hepatocyte ballooning, substantial reduction of steatosis, and reduced liver inflammation with a striking decrease in the number of macrophage crown-like structures; the resultant non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS) was 6.9 (range 6-7) indicated all vehicle-treated foz/foz mice (8/8) showed definite NASH. MBX-8025 reversed NASH in all foz/ foz mice (NAS 3.13; P<0.05), with only residual simple steatosis being present. MBX-8025 also repressed development of liver fibrosis, quantified by collagen densitometry and mRNA analyses. Conclusions: The selective PPAR-δ agonist MBX-8025 improves glucose tolerance and reverses diabetes, atherogenic dyslipidemia, hepatic lipid storage (including lipotoxic lipids), and NASH pathology in atherogenic diet-fed diabetic mice. MBX-8025 acts independently of weight reduction, appears to counter lipotoxicity related to insulin resistance, with accompanying reductions in liver inflammation and fibrosis. MBX-8025 provides a novel mechanism-based therapeutic agent to treat NASH.