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

Juncheng Wei, Yanzhi Yuan, Lu Chen, Yuanming Xu, Yuehui Zhang, Yajun Wang, Yanjie Yang, Clara Bien Peek, Lauren Diebold, Yi Yang, Beixue Gao, Chaozhi Jin, Johanna Melo-Cardenas, Navdeep S. Chandel, Donna D. Zhang, Hui Pan, Kezhong Zhang, Jian Wang (), Fuchu He () and Deyu Fang ()
Additional contact information
Juncheng Wei: Northwestern University Feinberg School of Medicine
Yanzhi Yuan: National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics
Lu Chen: Chinese Academy of Medical Science
Yuanming Xu: Northwestern University Feinberg School of Medicine
Yuehui Zhang: National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics
Yajun Wang: Northwestern University Feinberg School of Medicine
Yanjie Yang: Public Health Institute of Harbin Medical University
Clara Bien Peek: Northwestern University Feinberg School of Medicine
Lauren Diebold: Northwestern University Feinberg School of Mdicine
Yi Yang: Northwestern University Feinberg School of Medicine
Beixue Gao: Northwestern University Feinberg School of Medicine
Chaozhi Jin: National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics
Johanna Melo-Cardenas: Northwestern University Feinberg School of Medicine
Navdeep S. Chandel: Northwestern University Feinberg School of Mdicine
Donna D. Zhang: University of Arizona
Hui Pan: Chinese Academy of Medical Science
Kezhong Zhang: Wayne State University School of Medicine
Jian Wang: National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics
Fuchu He: National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics
Deyu Fang: Northwestern University Feinberg School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06091-7

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