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

Xiao-Yi Lu, Xiong-Jie Shi, Ao Hu, Ju-Qiong Wang, Yi Ding, Wei Jiang, Ming Sun, Xiaolu Zhao, Jie Luo, Wei Qi and Bao-Liang Song ()
Additional contact information
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

Nature, 2020, vol. 588, issue 7838, 479-484

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2928-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:588:y:2020:i:7838:d:10.1038_s41586-020-2928-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2928-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().