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

Yan Liu, Lin Jiang, Chengxin Sun, Nicole Ireland, Yatrik M. Shah, Yong Liu and Liangyou Rui ()
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Yan Liu: University of Michigan Medical School
Lin Jiang: University of Michigan Medical School
Chengxin Sun: University of Michigan Medical School
Nicole Ireland: University of Michigan Medical School
Yatrik M. Shah: University of Michigan Medical School
Yong Liu: Wuhan University
Liangyou Rui: University of Michigan Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05309-y

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