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Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

Authors
 Jung-Hwan Baek  ;  Myung Sup Kim  ;  Hye Ryeon Jung  ;  Min-Seon Hwang  ;  Chan-Ho Lee  ;  Dai Hoon Han  ;  Yong-Ho Lee  ;  Eugene C Yi  ;  Seung-Soon Im  ;  Ilseon Hwang  ;  Kyungeun Kim  ;  Joon-Yong Chung  ;  Kyung-Hee Chun 
Citation
 EXPERIMENTAL AND MOLECULAR MEDICINE, Vol.55(7) : 1520-1530, 2023-07 
Journal Title
EXPERIMENTAL AND MOLECULAR MEDICINE
ISSN
 1226-3613 
Issue Date
2023-07
MeSH
Animals ; Deubiquitinating Enzymes ; Diet, High-Fat / adverse effects ; Disease Models, Animal ; Lipids ; Liver / metabolism ; Liver Cirrhosis / metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Non-alcoholic Fatty Liver Disease* / genetics ; Non-alcoholic Fatty Liver Disease* / metabolism
Abstract
Nonalcoholic fatty liver disease (NAFLD) occurs due to the accumulation of fat in the liver, leading to fatal liver diseases such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Elucidation of the molecular mechanisms underlying NAFLD is critical for its prevention and therapy. Here, we observed that deubiquitinase USP15 expression was upregulated in the livers of mice fed a high-fat diet (HFD) and liver biopsies of patients with NAFLD or NASH. USP15 interacts with lipid-accumulating proteins such as FABPs and perilipins to reduce ubiquitination and increase their protein stability. Furthermore, the severity of NAFLD induced by an HFD and NASH induced by a fructose/palmitate/cholesterol/trans-fat (FPC) diet was significantly ameliorated in hepatocyte-specific USP15 knockout mice. Thus, our findings reveal an unrecognized function of USP15 in the lipid accumulation of livers, which exacerbates NAFLD to NASH by overriding nutrients and inducing inflammation. Therefore, targeting USP15 can be used in the prevention and treatment of NAFLD and NASH.
Files in This Item:
T202304632.pdf Download
DOI
10.1038/s12276-023-01036-7
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Myung Sup(김명섭)
Baek, Jung Hwan(백정환) ORCID logo https://orcid.org/0000-0002-2250-1557
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
Han, Dai Hoon(한대훈) ORCID logo https://orcid.org/0000-0003-2787-7876
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/196207
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