Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis

Nature Communications, Jul 2018

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.

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Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis

NATURE COMMUNICATIONS | Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis Yan Liu 0 Lin Jiang 0 Chengxin Sun 0 Nicole Ireland 0 Yatrik M. Shah 0 1 Yong Liu 2 Liangyou Rui 0 Department of Molecular & Integrative Physiology, University of Michigan Medical School , Ann Arbor, MI 48109 , USA 1 Department of Internal Medicine, University of Michigan Medical School , Ann Arbor, MI 48109 , USA 2 College of Life Sciences, the Institute for Advanced Studies, Wuhan University , Wuhan 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. - 1,2 :;, )( 0 9 8 7 6 5 4 3 2 1 P increases in an alarming pace due to the obesity epidemic1. revalence of nonalcoholic fatty liver disease (NAFLD) The outcomes of NAFLD are ominous, including insulin resistance, type 2 diabetes, dyslipidemia, cardiovascular disease, liver fibrosis, cirrhosis, and/or hepatocellular carcinoma1?3. Liver lipid levels are determined by an interplay between de novo lipogenesis, lipid uptake, fatty acid ? oxidation, and very lowdensity lipoprotein (VLDL) secretion. Notably, hepatic lipogenesis increases in NAFLD4,5, and genetic disruption of the hepatic lipogenic program prevents NAFLD6?8. Thus, inhibiting hepatic lipogenesis likely provides a therapeutic strategy for combatting NAFLD. Liver lipogenesis is regulated predominantly by metabolic hormone insulin. 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. Paradoxically, insulin resistance is associated with increased hepatic lipogenesis in obesity, contributing to NAFLD10. However, the underlying mechanism remains poorly understood. We recently reported that insulin upregulates adipose Snail1 that in turn suppresses expression of adipose triacylglycerol lipase (ATGL) and ATGL-mediated lipolysis11. Snail1 is a transcriptional repressor, and has been known to induce epithelial-tomesenchymal transition (EMT) during development or in cancer metastasis12?14. Snail1 has been well documented to epigenetically suppress expression of E-cadherin and claudin, thus promoting EMT15?18. Mechanistically, Snail1 binds via its N-terminal SNAG domain to several epigenetic enzymes, including histone deacetylases (HDACs) and histone methyltransferases, and recruit them to target promoters where these enzymes catalyze repressive histone modifications14,15. Notably, we found two reports that describe the potential action of hepatic Snail1 in liver injury and regeneration19,20; however, the metabolic function of hepatic Snail1 has not been explored. In this study, we provide proof of concept evidence showing that hepatic Snail1 is an unrecognized suppressor of de novo lipogenesis. It epigenetically represses expression of lipogenic enzymes. We further demonstrate that insulin robustly upregulates Snail1 which defines the noncanonical anti-lipogenic pathway. Thus, this work unravels a bifurcation of insulin signaling into the canonical lipogenic and the noncanonical anti-lipogenic arms. Results Insulin upregulates hepatic Snail1 via PI 3-kinase pathway. Given that insulin stimulates Snail1 expression in adipocytes11, we postulated that insulin might similarly upregulate Snail1 in hepatocytes. Indeed, insulin markedly increased Snail1 mRNA levels in both mouse primary hepatocytes and human HepG2 hepatocytes (Supplementary Fig. 1a, b), and substantially increased Snail1 protein levels in HepG2 hepatocytes (Fig. 1a). Likewise, insulin markedly increased the mRNA and protein levels of hepatic Snail1 in C57BL/6 mice (Supplementary Fig. 1c, d). Consistentl (...truncated)


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Yan Liu, Lin Jiang, Chengxin Sun, Nicole Ireland, Yatrik M. Shah, Yong Liu, Liangyou Rui. Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis, Nature Communications, 2018, Issue: 9, DOI: 10.1038/s41467-018-05309-y