Highlights
- •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
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Graphical abstract
Graphical Abstract
Abbreviations:
Hrd1 (HMG-CoA Reductase Degradation protein), Acly (ATP citrate lyase), NAFLD (nonalcoholic fatty liver disease), acetyl-CoA (acetyl coenzyme A), ERAD (endoplasmic reticulum-associated degradation), SREBP-1α (sterol regulatory element binding protein-1α), ChREBP (carbohydrate response element binding protein), GTT (glucose tolerance test), ITT (insulin tolerance test), PSM (peptide spectra matched to the protein), CHX (cycloheximid), Fasn (fatty acid synthase), PPARγ (peroxisome proliferator-activated receptor-γ), acetyl-CoA carboxylase 1 (Acc), OA (oleic acid), TG (Triglyceride), FFA (free fatty acid), PA (palmitic acid), Pck (phosphoenolpyruvate carboxy kinase), Pfkp (ATP-dependent 6-phosphofructokinase, platelet type), HFD (high-fat-diet), HOMA-IR (homeostatic model assessment of insulin resistance)Keywords
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Article Info
Publication History
Published online: September 01, 2020
Accepted:
August 27,
2020
Received in revised form:
August 25,
2020
Received:
April 22,
2020
Identification
Copyright
© 2020 Elsevier Inc. All rights reserved.
