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

doi:10.1038/s41586-020-2928-y

	Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis
	Lu, Xiao-Yi 1; Shi, Xiong-Jie 1; Hu, Ao 1; Wang, Ju-Qiong 1; Ding, Yi 1; Jiang, Wei 1; Sun, Ming 1; Zhao, Xiaolu 1; Luo, Jie 1; Qi, Wei2 ; Song, Bao-Liang 1
	2020-12-17
发表期刊	NATURE (IF:50.5[JCR-2023],54.4[5-Year])
ISSN	0028-0836
发表状态	已发表
DOI	10.1038/s41586-020-2928-y
摘要	Cholesterol is an essential lipid and its synthesis is nutritionally and energetically costly(1,2). In mammals, cholesterol biosynthesis increases after feeding and is inhibited under fasting conditions(3). 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.
收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Science Foundation China[91957103][91954203][31690102][32021003] ; Ministry of Science and Technology China[2016YFA0500100]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000588617900009
出版者	NATURE RESEARCH
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/124314
专题	生命科学与技术学院_PI研究组_戚炜组
通讯作者	Song, Bao-Liang
作者单位	1.Wuhan Univ, Inst Adv Studies, Frontier Sci Ctr Immunol & Metab, Hubei Key Lab Cell Homeostasis,Coll Life Sci, Wuhan, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Lu, Xiao-Yi,Shi, Xiong-Jie,Hu, Ao,et al. Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis[J]. NATURE,2020.
APA	Lu, Xiao-Yi.,Shi, Xiong-Jie.,Hu, Ao.,Wang, Ju-Qiong.,Ding, Yi.,...&Song, Bao-Liang.(2020).Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis.NATURE.
MLA	Lu, Xiao-Yi,et al."Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis".NATURE (2020).