Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
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,...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
|
| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-023-01036-7 |
| _version_ | 1826991213983563776 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Jung-Hwan Baek |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T17:09:50Z |
| format | Article |
| id | doaj.art-fa3fd4008685464f806a79d36788d5e5 |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2025-02-18T08:32:01Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-fa3fd4008685464f806a79d36788d5e52024-11-03T12:11:20ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132023-07-015571520153010.1038/s12276-023-01036-7Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitisJung-Hwan Baek0Myung Sup Kim1Hye Ryeon Jung2Min-Seon Hwang3Chan-ho Lee4Dai Hoon Han5Yong-ho Lee6Eugene C. Yi7Seung-Soon Im8Ilseon Hwang9Kyungeun Kim10Joon-Yong Chung11Kyung-Hee Chun12Department of Biochemistry & Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineDepartment of Biochemistry & Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineDepartment of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National UniversityDepartment of Biochemistry & Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineDepartment of Biochemistry & Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineDepartment of Surgery, Yonsei University College of MedicineDepartment of Internal Medicine, Yonsei University College of MedicineDepartment of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National UniversityDepartment of Physiology, Keimyung University School of MedicineDepartment of Pathology, Keimyung University School of MedicineDepartment of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of MedicineLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDepartment of Biochemistry & Molecular Biology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineAbstract 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.https://doi.org/10.1038/s12276-023-01036-7 |
| spellingShingle | 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 Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis Experimental and Molecular Medicine |
| title | Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis |
| title_full | Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis |
| title_fullStr | Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis |
| title_full_unstemmed | Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis |
| title_short | Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis |
| title_sort | ablation of the deubiquitinase usp15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis |
| url | https://doi.org/10.1038/s12276-023-01036-7 |
| work_keys_str_mv | AT junghwanbaek ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT myungsupkim ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT hyeryeonjung ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT minseonhwang ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT chanholee ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT daihoonhan ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT yongholee ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT eugenecyi ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT seungsoonim ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT ilseonhwang ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT kyungeunkim ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT joonyongchung ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis AT kyungheechun ablationofthedeubiquitinaseusp15amelioratesnonalcoholicfattyliverdiseaseandnonalcoholicsteatohepatitis |