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ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes.

Nat Commun. 2018 Sep 10;9(1):3659
Juncheng Wei 1 , Yanzhi Yuan 2 , Lu Chen 3 , Yuanming Xu 1 , Yuehui Zhang 2 , Yajun Wang 1 , Yanjie Yang 4 , Clara Bien Peek 5 , Lauren Diebold 6 , Yi Yang 1 , Beixue Gao 1 , Chaozhi Jin 2 , Johanna Melo-Cardenas 1 , Navdeep S Chandel 6 , Donna D Zhang 7 , Hui Pan 3 , Kezhong Zhang 8 , Jian Wang 9 , Fuchu He 10 , Deyu Fang 11
Juncheng Wei 1 , Yanzhi Yuan 2 , Lu Chen 3 , Yuanming Xu 1 , Yuehui Zhang 2 , Yajun Wang 1 , Yanjie Yang 4 , Clara Bien Peek 5 , Lauren Diebold 6 , Yi Yang 1 , Beixue Gao 1 , Chaozhi Jin 2 , Johanna Melo-Cardenas 1 , Navdeep S Chandel 6 , Donna D Zhang 7 , Hui Pan 3 , Kezhong Zhang 8 , Jian Wang 9 , Fuchu He 10 , Deyu Fang 11
+ et al

[No authors listed]

Author information
  • 1 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 2 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 102206, Beijing, China.
  • 3 Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, 100730, Beijing, China.
  • 4 Department of Medical Psychology, Public Health Institute of Harbin Medical University, 150081, Harbin, China.
  • 5 Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
  • 6 Department of Medicine, Northwestern University Feinberg School of Mdicine, Chicago, IL, 60611, USA.
  • 7 Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, 85721, USA.
  • 8 Center for Molecular Medicine and Genetics, Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
  • 9 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 102206, Beijing, China. wangjian@bmi.ac.cn.
  • 10 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 102206, Beijing, China. hefc@bmi.ac.cn.
  • 11 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. fangd@northwestern.edu.

摘要


The HMG-CoA reductase degradation protein 1 (HRD1) has been identified as a key enzyme for endoplasmic reticulum-associated degradation of misfolded proteins, but its organ-specific physiological functions remain largely undefined. Here we show that mice with HRD1 deletion specifically in the liver display increased energy expenditure and are resistant to HFD-induced obesity and liver steatosis and insulin resistance. Proteomic analysis identifies a HRD1 interactome, a large portion of which includes metabolic regulators. Loss of HRD1 results in elevated ENTPD5, CPT2, RMND1, and HSD17B4 protein levels and a consequent hyperactivation of both AMPK and AKT pathways. Genome-wide mRNA sequencing revealed that HRD1-deficiency reprograms liver metabolic gene expression profiles, including suppressing genes involved in glycogenesis and lipogenesis and upregulating genes involved in glycolysis and fatty acid oxidation. We propose HRD1 as a liver metabolic regulator and a potential drug target for obesity, fatty liver disease, and insulin resistance associated with the metabolic syndrome.