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

Author

Listed:
  • 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
    University of Michigan Medical School)

  • Yong Liu

    (Wuhan University)

  • Liangyou Rui

    (University of Michigan Medical School
    University of Michigan Medical School)

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.

Suggested Citation

  • Yan Liu & Lin Jiang & Chengxin Sun & Nicole Ireland & Yatrik M. Shah & Yong Liu & Liangyou Rui, 2018. "Insulin/Snail1 axis ameliorates fatty liver disease by epigenetically suppressing lipogenesis," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05309-y
    DOI: 10.1038/s41467-018-05309-y
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    Cited by:

    1. Li Weng & Wen-Shuai Tang & Xu Wang & Yingyun Gong & Changqin Liu & Ni-Na Hong & Ying Tao & Kuang-Zheng Li & Shu-Ning Liu & Wanzi Jiang & Ying Li & Ke Yao & Li Chen & He Huang & Yu-Zheng Zhao & Ze-Ping, 2024. "Surplus fatty acid synthesis increases oxidative stress in adipocytes and induces lipodystrophy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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