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, Lauren Diebold, Yi Yang, Beixue Gao, Chaozhi Jin, Johanna Melo-Cardenas, Navdeep Chandel, Donna D. Zhang, Hui Pan, Kezhong Zhang, Jian Wang, Fuchu He, Deyu Fang*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

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

Fingerprint

Hydroxymethylglutaryl CoA Reductases
metabolism
Ligases
Ubiquitin
liver
Metabolism
Liver
Proteolysis
enzymes
degradation
proteins
Degradation
Enzymes
Proteins
obesity
Fatty Liver
insulin
Insulin Resistance
Genes
regulators

ASJC Scopus subject areas

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

Cite this

Wei, Juncheng ; Yuan, Yanzhi ; Chen, Lu ; Xu, Yuanming ; Zhang, Yuehui ; Wang, Yajun ; Yang, Yanjie ; Bien, Clara ; Diebold, Lauren ; Yang, Yi ; Gao, Beixue ; Jin, Chaozhi ; Melo-Cardenas, Johanna ; Chandel, Navdeep ; Zhang, Donna D. ; Pan, Hui ; Zhang, Kezhong ; Wang, Jian ; He, Fuchu ; Fang, Deyu. / ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes. In: Nature communications. 2018 ; Vol. 9, No. 1.
@article{b3742d5a83ba4d71933d14351892b16e,
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 Clara Bien and Lauren Diebold and Yi Yang and Beixue Gao and Chaozhi Jin and Johanna Melo-Cardenas and Navdeep Chandel and Zhang, {Donna D.} and Hui Pan and Kezhong Zhang and Jian Wang and Fuchu He and Deyu Fang",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-06091-7",
language = "English (US)",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

Wei, J, Yuan, Y, Chen, L, Xu, Y, Zhang, Y, Wang, Y, Yang, Y, Bien, C, Diebold, L, Yang, Y, Gao, B, Jin, C, Melo-Cardenas, J, Chandel, N, 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

ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes. / Wei, Juncheng; Yuan, Yanzhi; Chen, Lu; Xu, Yuanming; Zhang, Yuehui; Wang, Yajun; Yang, Yanjie; Bien, Clara; Diebold, Lauren; Yang, Yi; Gao, Beixue; Jin, Chaozhi; Melo-Cardenas, Johanna; Chandel, Navdeep; Zhang, Donna D.; Pan, Hui; Zhang, Kezhong; Wang, Jian; He, Fuchu; Fang, Deyu.

In: Nature communications, Vol. 9, No. 1, 3659, 01.12.2018.

Research output: Contribution to journalArticle

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 - Bien, Clara

AU - Diebold, Lauren

AU - Yang, Yi

AU - Gao, Beixue

AU - Jin, Chaozhi

AU - Melo-Cardenas, Johanna

AU - Chandel, Navdeep

AU - Zhang, Donna D.

AU - Pan, Hui

AU - Zhang, Kezhong

AU - Wang, Jian

AU - He, Fuchu

AU - Fang, Deyu

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.

UR - http://www.scopus.com/inward/record.url?scp=85053183049&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053183049&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06091-7

DO - 10.1038/s41467-018-06091-7

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 3659

ER -