TY - JOUR
T1 - ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes
AU - Wei, Juncheng
AU - Yuan, Yanzhi
AU - Chen, Lu
AU - Xu, Yuanming
AU - Zhang, Yuehui
AU - Wang, Yajun
AU - Yang, Yanjie
AU - Peek, Clara Bien
AU - Diebold, Lauren
AU - Yang, Yi
AU - Gao, Beixue
AU - Jin, Chaozhi
AU - Melo-Cardenas, Johanna
AU - Chandel, Navdeep S.
AU - Zhang, Donna D.
AU - Pan, Hui
AU - Zhang, Kezhong
AU - Wang, Jian
AU - He, Fuchu
AU - Fang, Deyu
N1 - Funding Information:
This work was supported by grants from the Special Funds for Major State Basic Research of China (2014CBA02001) to F.H. and J.W. and the National Institutes of Health (NIH) R01 grants (AI079056, AI108634, and AR006634) to D.F., NIH grant DK090313 to K.Z., and NIH grant 5P01AG049665 to N.S.C.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-06091-7
DO - 10.1038/s41467-018-06091-7
M3 - Article
C2 - 30201971
AN - SCOPUS:85053183049
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3659
ER -
