Insulin stimulates hepatic lipogenesis that drives nonalcoholic fatty liver disease (NAFLD). Paradoxically, insulin resistance is associated with increased hepatic lipogenesis in obesity, and the underlying mechanism remains poorly understood. Here, we delineate an insulin-PI 3-kinase-Snail1 pathway that links metabolic signals to epigenetic reprogramming of de novo lipogenesis in the liver. We found that insulin robustly upregulated Snail1 in both primary hepatocytes and liver in a PI 3-kinase-dependent manner. Notably, the hepatic insulin-PI 3-kinase-Snail1 pathway was severely impaired in obesity. Overexpression of Snail1 blocked, whereas deletion of endogenous Snail1 enhanced, insulin-stimulated lipogenesis in hepatocytes. Hepatocyte-specific deletion of Snail1 exacerbated, whereas liver-specific overexpression of Snail1 ameliorated, dietary NAFLD in mice. Ablation of hepatic Snail1 also attenuated NAFLD-associated insulin resistance and glucose intolerance; conversely, liver-specific overexpression had the opposite effect. Mechanistically, Snail1 bound to the fatty acid synthase (Fasn) promoter and repressed Fasn promoter activity through histone modifications. Our data suggest that insulin pathways bifurcate into the canonical lipogenic and the noncanonical Snail1 two arms wherein the Snail1 arm puts a brake on the lipogenic arm, curbing excessive lipogenesis, liver steatosis, and lipotoxicity. Thus, insulin-resistance-induced impairment in the Snail1 arm contributes to increased lipogenesis in obesity.
Y. Liu: None. N.M. Ireland: None. L. Jiang: None. L. Rui: None.