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, Deyu Fang

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Article number3659
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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