Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis
Year: 2018
Type: article
Abstract: Insulin stimulates lipogenesis but insulin resistance is also associated with increased hepatic lipogenesis in obesity. However, the underlying mechanism remains poorly characterized. Here, we show a noncanonical insulin-Snail1 pathway that suppresses lipogenesis. Insulin robustly upregulates zinc-finger protein Snail1 in a PI 3-kinase-dependent manner. In obesity, the hepatic insulin-Snail1 cascade is impaired due to insulin resistance. Hepatocyte-specific deletion of Snail1 enhances insulin-stimulated lipogenesis in hepatocytes, exacerbates dietary NAFLD in mice, and attenuates NAFLD-associated insulin resistance. Liver-specific overexpression of Snail1 has the opposite effect. Mechanistically, Snail1 binds to the fatty acid synthase promoter and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27, thereby repressing fatty acid synthase promoter activity. Our data suggest that insulin pathways bifurcate into canonical (lipogenic) and noncanonical (anti-lipogenesis by Snail1) two arms. The noncanonical arm counterbalances the canonical arm through Snail1-elicited epigenetic suppression of lipogenic genes. Impairment in the insulin-Snail1 arm may contribute to NAFLD in obesity.
Source: Nature Communications
Institutions: University of Michigan, Wuhan University, Michigan Medicine
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: University of Michigan Center for Gastrointestinal Research, G1516671061, Role of inflammation and cellular stress in the pathogenesis of type 2 diabetes, G1619971191, Michigan Diabetes Research and Training Center, G2273956856, G2294010916, G2780977004, G301048564, G4308227006, The role of hypothalamic Slug in the regulation of leptin sensitivity, energy balance, and body weight, G6124142866, G6165898751, G7452586543, G7701448428, Role of NF-kB-induce kinase (NIK) in liver diseases, G8373452122, Transcriptional Regulation of Metabolism, G9000002557, G9000137216, G9000213749, G9000270911, G9000301458, Control of iron absorption by intestinal HIF2 in iron and hematological disorders, Michigan Diabetes Research Center (MDRC)
OpenAlex ID: W2878411673