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

doi:10.1038/s41467-018-06091-7

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

50 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 language	English (US)
Article number	3659
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06091-7
State	Published - Dec 1 2018

Funding

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.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-06091-7

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Wei, J., Yuan, Y., Chen, L., Xu, Y., Zhang, Y., Wang, Y., Yang, Y., Peek, C. B., Diebold, L., Yang, Y., Gao, B., Jin, C., Melo-Cardenas, J., Chandel, N. S., Zhang, D. D., Pan, H., Zhang, K., Wang, J., He, F., & Fang, D. (2018). ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes. Nature communications, 9(1), Article 3659. https://doi.org/10.1038/s41467-018-06091-7

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title = "ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes",

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.",

author = "Juncheng Wei and Yanzhi Yuan and Lu Chen and Yuanming Xu and Yuehui Zhang and Yajun Wang and Yanjie Yang and Peek, {Clara Bien} and Lauren Diebold and Yi Yang and Beixue Gao and Chaozhi Jin and Johanna Melo-Cardenas and Chandel, {Navdeep S.} and Zhang, {Donna D.} and Hui Pan and Kezhong Zhang and Jian Wang and Fuchu He and Deyu Fang",

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Wei, J, Yuan, Y, Chen, L, Xu, Y, Zhang, Y, Wang, Y, Yang, Y, Peek, CB , Diebold, L, Yang, Y, Gao, B, Jin, C, Melo-Cardenas, J , Chandel, NS, Zhang, DD, Pan, H, Zhang, K, Wang, J, He, F & Fang, D 2018, 'ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes', Nature communications, vol. 9, no. 1, 3659. https://doi.org/10.1038/s41467-018-06091-7

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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

PY - 2018/12/1

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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.

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

Abstract

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UN SDGs

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