1751-P: Induction of Sirt1-AMPK Pathway by GLP-1RA Liraglutide Reduces Hepatic Lipid Accumulation and Insulin Resistance

Abstract

Hepatic insulin resistance is associated with metabolic disorders such as type 2 diabetes (T2D), which often develops after the accumulation of lipids in the liver. In particular, elevated plasma levels of free fatty acids (FFA) are the primary sources of hepatic lipid accumulation that contributes to the development of insulin-resistant states. Interestingly, one gut-derived incretin hormone receptor called glucagon-like peptide 1 (GLP-1) receptor, is highly expressed on human hepatocytes. Although GLP-1-based therapies have shown great benefit in the treatment of T2D with improved glycemic control, they also additionally possess extrapancreatic metabolic actions including that in the liver. Studies have demonstrated that GLP-1 receptor agonist (GLP-1 RA) may reverse the progression of nonalcoholic fatty liver disease (NAFLD), a T2D-related disorder characterized by hepatic lipid accumulation. This suggests GLP-1 RA may be effective treatment options for NAFLD and associated hepatic disorders, but the mechanism behind this is still unknown. In the present study, we investigated the function of GLP-1 signaling in protecting human HepG2 hepatocytes from FFA-related damages. By using high-content analysis (HCA) cellomics techniques, we found that treatment with the GLP-1 RA liraglutide has shown a significant lipid droplets-lowering effect in hepatocytes exposure to high levels of FFAs. Liraglutide also decreased free radical generation and subsequently reduced oxidative stress, thus alleviated FFA induced inflammation. Moreover, activation of AMPK by liraglutide increased insulin sensitivity and improved oxidative stress-induced senescence by inducing Sirt1 pathway. Collectively, our results demonstrated that hepatic GLP-1 signaling may play a crucial role in the regulation of lipid deposits and related disorders in liver. This suggests the potential therapeutic usage of GLP-1 RA-based strategies for patients with T2D who also have NAFLD. Disclosure C. Huang: None. H. Li: None. C. Peng: None. E. Kornelius: None. Y. Yang: None. L. Chiu: None. C. Lin: None. Funding Ministry of Science and Technology of Taiwan (108-2314-B-040-021-MY3)