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.
Highlights
Insulin stimulates lipogenesis but insulin resistance is associated with increased hepatic lipogenesis in obesity
Insulin resistance is associated with increased hepatic lipogenesis in obesity, contributing to NAFLD10
We recently reported that insulin upregulates adipose Snail[1] that in turn suppresses expression of adipose triacylglycerol lipase (ATGL) and ATGL-mediated lipolysis[11]
Summary
Insulin stimulates lipogenesis but insulin resistance is associated with increased hepatic lipogenesis in obesity. Our data suggest that insulin pathways bifurcate into canonical (lipogenic) and noncanonical (anti-lipogenesis by Snail1) two arms. Insulin stimulates the canonical lipogenic pathway, including activation of lipogenic transcription factors liver X receptor (Lxr), Srebp-1c, and upstream stimulatory factor-1 (Usf-1)[5,9]. These nuclear proteins activate expression of lipogenic enzymes ATP citrate lyase (Acl), acetyl coenzyme A carboxylase 1 (Acc1), and/or fatty acid synthase (Fasn)[5]. We provide proof of concept evidence showing that hepatic Snail[1] is an unrecognized suppressor of de novo lipogenesis It epigenetically represses expression of lipogenic enzymes. This work unravels a bifurcation of insulin signaling into the canonical lipogenic and the noncanonical anti-lipogenic arms
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