Neddylation of sterol regulatory element-binding protein 1c is a potential therapeutic target for nonalcoholic fatty liver treatment

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for progression of steatohepatitis, liver cirrhosis, and liver cancer. Although pathological condition of NAFLD, which arises from an excessive accumulation of triglyceride in the liver, is accompanied by elevated sterol regulatory element-bi...

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Bibliographic Details
Published in:Cell death & disease 2020-04, Vol.11 (4), p.283, Article 283
Main Authors: Ju, Uk-Il, Jeong, Do-Won, Seo, Jieun, Park, Jun Bum, Park, Jong-Wan, Suh, Kyung-Suk, Kim, Jae Bum, Chun, Yang-Sook
Format: Article
Language:English
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Antibodies
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cirrhosis
Fatty liver
High fat diet
Humans
Immunology
Life Sciences
Liver
Liver cancer
Liver cirrhosis
Liver diseases
NEDD8 Protein - genetics
NEDD8 Protein - metabolism
Non-alcoholic Fatty Liver Disease - therapy
Proteins
Risk Factors
Steatosis
Sterol Regulatory Element Binding Protein 1 - metabolism
Sterol regulatory element-binding protein
Sterol regulatory element-binding protein 1c
Sterols
Therapeutic applications
Transfection
Trimeprazine
Ubiquitination
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Summary:Nonalcoholic fatty liver disease (NAFLD) is a risk factor for progression of steatohepatitis, liver cirrhosis, and liver cancer. Although pathological condition of NAFLD, which arises from an excessive accumulation of triglyceride in the liver, is accompanied by elevated sterol regulatory element-binding protein 1c (SREBP1c) level, it is largely unknown which factors are involved in the modification of SREBP1c. In this study, we discovered that neddylation of SREBP1c competes with its ubiquitination and stabilizes SREBP1c protein level, and eventually promotes hepatic steatosis. We also demonstrated that human homolog of mouse double minute 2 (HDM2) acts as an E3 neddylation ligase of SREBP1c. Further, treatment with the neddylation inhibitor, MLN4924, attenuates high-fat diet-induced hepatic steatosis by reducing the levels of SREBP1c protein and hepatic triglyceride. Our results indicate that the blockade of SREBP1c neddylation could be a novel approach in the defense against NAFLD.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-020-2472-6