281-LB: PBI-4547 Orchestrates a Cross Talk between Liver and White Adipose Tissues to Correct Metabolic Reprogramming

Abstract

Introduction: Nonalcoholic Fatty Liver Diseases (NAFLD), characterized by fatty acid and glucose metabolism dysregulation, is highly prevalent in all regions of the world. PBI-4547 is an orally active compound which displays pleiotropic activities and has been shown to reduce NASH, diabetes and fibrosis in different rodent models. The goal of the current study was to investigate the effects of PBI-4547 in a mouse model of high-fat diet-induced obesity and metabolic syndrome. Methods: C57BL/6 mice were fed with either a standard or a high-fat diet (HFD, Harlan, TD.06414) for 14 weeks. Mice fed with the HFD were then treated or not with PBI-4547 (10 mg/kg, oral once a day) for 6 weeks. Liver/WAT histology and mRNA gene profile were examined. HepG2 hepatocytes were also used for in vitro experiments. Blood glucose, serum insulin level, serum triglyceride and adiponectin were followed over the 6 weeks of treatment. Results: PBI-4547 treatment led to a significant reduction of hepatic steatosis, ballooning and total NAFLD score. Inflammation and fibrosis in white adipose tissues were also significantly reduced by PBI-4547. Adiponectin levels were also increased by PBI-4547. Metabolomic study from liver extracts revealed that PBI-4547 restored back to normal the levels of amino acids, Krebs cycle and energy-related intermediates. Uncoupling Proteins (Ucp2/3 in liver and Ucp1 in WAT) were also increased by PBI-4547 suggesting that PBI-4547 could affect mitochondria and increase energy expenditure. Oxygen consumption rate analyses confirmed that PBI-4547 reduces Oxphos-related ATP production and increased proton leak in HepG2 hepatocytes. In such way, PBI-4547 increased glucose and fatty acid metabolism improving insulin resistance and β-cell function. Conclusions: These results indicate that PBI-4547 offers the potential as a novel therapy for NAFLD, diabetes and associated metabolic syndrome. Disclosure J. Simard: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Thibodeau: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Leduc: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Laverdure: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. R. Corpuz: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc.