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Feeding induces cholesterol biosynthesis via the mTORC1–USP20–HMGCR axis

Author

Listed:
  • Xiao-Yi Lu

    (Wuhan University)

  • Xiong-Jie Shi

    (Wuhan University)

  • Ao Hu

    (Wuhan University)

  • Ju-Qiong Wang

    (Wuhan University)

  • Yi Ding

    (Wuhan University)

  • Wei Jiang

    (Wuhan University)

  • Ming Sun

    (Wuhan University)

  • Xiaolu Zhao

    (Wuhan University)

  • Jie Luo

    (Wuhan University)

  • Wei Qi

    (ShanghaiTech University)

  • Bao-Liang Song

    (Wuhan University)

Abstract

Cholesterol is an essential lipid and its synthesis is nutritionally and energetically costly1,2. In mammals, cholesterol biosynthesis increases after feeding and is inhibited under fasting conditions3. However, the regulatory mechanisms of cholesterol biosynthesis at the fasting–feeding transition remain poorly understood. Here we show that the deubiquitylase ubiquitin-specific peptidase 20 (USP20) stabilizes HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthetic pathway, in the feeding state. The post-prandial increase in insulin and glucose concentration stimulates mTORC1 to phosphorylate USP20 at S132 and S134; USP20 is recruited to the HMGCR complex and antagonizes its degradation. The feeding-induced stabilization of HMGCR is abolished in mice with liver-specific Usp20 deletion and in USP20(S132A/S134A) knock-in mice. Genetic deletion or pharmacological inhibition of USP20 markedly decreases diet-induced body weight gain, reduces lipid levels in the serum and liver, improves insulin sensitivity and increases energy expenditure. These metabolic changes are reversed by expression of the constitutively stable HMGCR(K248R). This study reveals an unexpected regulatory axis from mTORC1 to HMGCR via USP20 phosphorylation and suggests that inhibitors of USP20 could be used to lower cholesterol levels to treat metabolic diseases including hyperlipidaemia, liver steatosis, obesity and diabetes.

Suggested Citation

  • Xiao-Yi Lu & Xiong-Jie Shi & Ao Hu & Ju-Qiong Wang & Yi Ding & Wei Jiang & Ming Sun & Xiaolu Zhao & Jie Luo & Wei Qi & Bao-Liang Song, 2020. "Feeding induces cholesterol biosynthesis via the mTORC1–USP20–HMGCR axis," Nature, Nature, vol. 588(7838), pages 479-484, December.
  • Handle: RePEc:nat:nature:v:588:y:2020:i:7838:d:10.1038_s41586-020-2928-y
    DOI: 10.1038/s41586-020-2928-y
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    Cited by:

    1. Yumeng Peng & Qiang Zeng & Luming Wan & Enhao Ma & Huilong Li & Xiaopan Yang & Yanhong Zhang & Linfei Huang & Haotian Lin & Jiangyue Feng & Yixin Xu & Jingfei Li & Muyi Liu & Jing Liu & Changqin Lin &, 2021. "GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Weitao Zhang & Junfeng Lu & Lianshun Feng & Hanyue Xue & Shiyang Shen & Shuiqing Lai & PingPing Li & Ping Li & Jian Kuang & Zhiwei Yang & Xiaojun Xu, 2024. "Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Zitao Zhao & Yanhong Guo & Lei Zhuang & Yongbao Wu & Jing Liu & Junting Cao & Zhanyue Wu & Zhiguo Wen, 2023. "Effects of the Dietary Replacement of Soybean Oil with Rubber Seed Oil on the Growth Performance, Carcass Trait, and Status of Lipid Metabolism in Pekin Ducks," Agriculture, MDPI, vol. 13(9), pages 1-12, August.

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