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Hrd1-mediated ACLY ubiquitination alleviate NAFLD in db/db mice

The functions of Acly in regulating nonalcoholic fatty liver disease (NAFLD) have been identified; however, the dynamic control of Acly expression under the pathological state of metabolic disorders has not been fully elucidated. Previous studies reported an ubiquitin-proteasome–mediated degradation...

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Published in:Metabolism, clinical and experimental clinical and experimental, 2021-01, Vol.114, p.154349-154349, Article 154349
Main Authors: Li, Kai, Zhang, Kaini, Wang, Hai, Wu, Yangyang, Chen, Nuoqi, Chen, Jinfeng, Qiu, Chen, Cai, Pengpeng, Li, Min, Liang, Xiubin, Su, Dongming
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container_title Metabolism, clinical and experimental
container_volume 114
creator Li, Kai
Zhang, Kaini
Wang, Hai
Wu, Yangyang
Chen, Nuoqi
Chen, Jinfeng
Qiu, Chen
Cai, Pengpeng
Li, Min
Liang, Xiubin
Su, Dongming
description The functions of Acly in regulating nonalcoholic fatty liver disease (NAFLD) have been identified; however, the dynamic control of Acly expression under the pathological state of metabolic disorders has not been fully elucidated. Previous studies reported an ubiquitin-proteasome–mediated degradation of Acly, but the mechanism is still largely unknown. Co-IP–based mass spectrum (MS/MS) assays were performed in HepG2 and Hepa1-6 hepatocytes and mouse liver tissue. The protein-protein interaction and ubiquitin modification of Hrd1 on Acly were confirmed by co-IP based immuno-blotting. Acetyl-CoA levels and lipogenesis rates were determined. The roles of Hrd1 on NAFLD and insulin resistance were tested by adenovirus-mediated overexpression in db/db mice or in separated primary hepatocytes. Hrd1, a subunit of the endoplasmic reticulum-associated degradation (ERAD) complex, interacted with and ubiquitinated Acly, thereby reducing its protein level. Hrd1 suppressed the acetyl-CoA level and inhibited lipogenesis through an Acly-dependent pathway. The expression of hepatic Hrd1 was negatively associated with NAFLD, whereas overexpression of Hrd1 ameliorated hepatic steatosis and enhanced insulin sensitivity, both in db/db mice and in separated mouse primary hepatocytes. Our results suggest that Acly, a master enzyme that regulates lipogenesis, is degraded by Hrd1 through ubiquitin modification. The activation of Hrd1 in hepatocytes might therefore represent a strategic approach for NAFLD therapy. [Display omitted] •Hrd1 ubiquitinates and degrades Acly, a key enzyme of de novo lipogenesis.•Hrd1 suppress lipogenesis and reduce Acetyl-CoA through downregulation of Acly.•Expression level of Hrd1 is negatively associated with liver steatosis.•Forced expression of Hrd1 reversed fatty liver and insulin resistance in db/db mice.
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Previous studies reported an ubiquitin-proteasome–mediated degradation of Acly, but the mechanism is still largely unknown. Co-IP–based mass spectrum (MS/MS) assays were performed in HepG2 and Hepa1-6 hepatocytes and mouse liver tissue. The protein-protein interaction and ubiquitin modification of Hrd1 on Acly were confirmed by co-IP based immuno-blotting. Acetyl-CoA levels and lipogenesis rates were determined. The roles of Hrd1 on NAFLD and insulin resistance were tested by adenovirus-mediated overexpression in db/db mice or in separated primary hepatocytes. Hrd1, a subunit of the endoplasmic reticulum-associated degradation (ERAD) complex, interacted with and ubiquitinated Acly, thereby reducing its protein level. Hrd1 suppressed the acetyl-CoA level and inhibited lipogenesis through an Acly-dependent pathway. The expression of hepatic Hrd1 was negatively associated with NAFLD, whereas overexpression of Hrd1 ameliorated hepatic steatosis and enhanced insulin sensitivity, both in db/db mice and in separated mouse primary hepatocytes. Our results suggest that Acly, a master enzyme that regulates lipogenesis, is degraded by Hrd1 through ubiquitin modification. The activation of Hrd1 in hepatocytes might therefore represent a strategic approach for NAFLD therapy. [Display omitted] •Hrd1 ubiquitinates and degrades Acly, a key enzyme of de novo lipogenesis.•Hrd1 suppress lipogenesis and reduce Acetyl-CoA through downregulation of Acly.•Expression level of Hrd1 is negatively associated with liver steatosis.•Forced expression of Hrd1 reversed fatty liver and insulin resistance in db/db mice.</description><identifier>ISSN: 0026-0495</identifier><identifier>EISSN: 1532-8600</identifier><identifier>DOI: 10.1016/j.metabol.2020.154349</identifier><identifier>PMID: 32888949</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acly stability ; Animals ; ATP Citrate (pro-S)-Lyase - metabolism ; Hep G2 Cells ; Hepatocytes - metabolism ; Hrd1 ; Humans ; Insulin resistance ; Insulin Resistance - physiology ; Lipogenesis - physiology ; Liver - metabolism ; Liver steatosis ; Mice ; Non-alcoholic Fatty Liver Disease - metabolism ; Obesity - metabolism ; Tandem Mass Spectrometry ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination ; Ubiquitination - physiology</subject><ispartof>Metabolism, clinical and experimental, 2021-01, Vol.114, p.154349-154349, Article 154349</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. 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however, the dynamic control of Acly expression under the pathological state of metabolic disorders has not been fully elucidated. Previous studies reported an ubiquitin-proteasome–mediated degradation of Acly, but the mechanism is still largely unknown. Co-IP–based mass spectrum (MS/MS) assays were performed in HepG2 and Hepa1-6 hepatocytes and mouse liver tissue. The protein-protein interaction and ubiquitin modification of Hrd1 on Acly were confirmed by co-IP based immuno-blotting. Acetyl-CoA levels and lipogenesis rates were determined. The roles of Hrd1 on NAFLD and insulin resistance were tested by adenovirus-mediated overexpression in db/db mice or in separated primary hepatocytes. Hrd1, a subunit of the endoplasmic reticulum-associated degradation (ERAD) complex, interacted with and ubiquitinated Acly, thereby reducing its protein level. Hrd1 suppressed the acetyl-CoA level and inhibited lipogenesis through an Acly-dependent pathway. The expression of hepatic Hrd1 was negatively associated with NAFLD, whereas overexpression of Hrd1 ameliorated hepatic steatosis and enhanced insulin sensitivity, both in db/db mice and in separated mouse primary hepatocytes. Our results suggest that Acly, a master enzyme that regulates lipogenesis, is degraded by Hrd1 through ubiquitin modification. The activation of Hrd1 in hepatocytes might therefore represent a strategic approach for NAFLD therapy. [Display omitted] •Hrd1 ubiquitinates and degrades Acly, a key enzyme of de novo lipogenesis.•Hrd1 suppress lipogenesis and reduce Acetyl-CoA through downregulation of Acly.•Expression level of Hrd1 is negatively associated with liver steatosis.•Forced expression of Hrd1 reversed fatty liver and insulin resistance in db/db mice.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32888949</pmid><doi>10.1016/j.metabol.2020.154349</doi><tpages>1</tpages></addata></record>
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subjects Acly stability
Animals
ATP Citrate (pro-S)-Lyase - metabolism
Hep G2 Cells
Hepatocytes - metabolism
Hrd1
Humans
Insulin resistance
Insulin Resistance - physiology
Lipogenesis - physiology
Liver - metabolism
Liver steatosis
Mice
Non-alcoholic Fatty Liver Disease - metabolism
Obesity - metabolism
Tandem Mass Spectrometry
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Ubiquitination - physiology
title Hrd1-mediated ACLY ubiquitination alleviate NAFLD in db/db mice
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