Regulation of Hepatic Insulin Sensitivity and Hepatic Steatosis by ULK1

• DOI: 10.2337/db18-1863-p
• Publication Date: 2018-06-22T18:57:32Z
• Authors: YOUNGDO KOO; MICHAEL P. GARNEAU; QUANJIANG ZHANG; E. DALE ABEL
• Keywords: ULK1; FOXO1; Steatosis

Hepatic insulin resistance (IR) plays a central role in the pathophysiology of impaired glucose tolerance, type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) steatohepatitis (NASH), which is emerging as major cause failure hepatocellular carcinoma. Impaired autophagy may also contribute to hepatic resistance, but interactions between sensitivity are incompletely understood. The Unc-51 Like Autophagy Activating Kinase 1 (ULK1) an early stage autophagosome formation related kinase that activated selective be independent nutrient or energy status. We observed addition its regulation, ULK1 directly regulate signaling by modulating AKT dephosphorylation. Specifically, silencing significantly impairs insulin-stimulated activation GSK3β hepatocytes absence significant changes autophagy. To understand action specific knock-out mice were generated. Body weight increased L-ULK1KO relative wild on normal chow diet 60% high fat diet. L-ULK1 KO exhibited tolerance resistance. Serum concentrations insulin, triglyceride, cholesterol, AST ALT increased. Phosphorylation levels FOXO1 FOXO3a decreased concert with expression PEPCK G6pase production. In contrast, L-ULK2 phenotypically normal. Thus, independently regulates homeostasis. Disclosure Y. Koo: None. M.P. Garneau: Q. Zhang: E. Abel: