USP13 ameliorates nonalcoholic fatty liver disease through inhibiting the activation of TAK1.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Non-alcoholic Fatty Liver Disease*/metabolism ; Non-alcoholic Fatty Liver Disease*/pathology ; MAP Kinase Kinase Kinases*/metabolism ; Ubiquitin-Specific Proteases*/metabolism ; Mice, Inbred C57BL* ; Diet, High-Fat*; Inflammation/pathology ; Hepatocytes/metabolism ; Animals ; Humans ; Male ; Enzyme Activation ; Mice, Knockout ; Mice ; Cell Line ; Ubiquitination ; MAP Kinase Kinase Kinase 7

Background: The molecular mechanisms underlying nonalcoholic fatty liver disease (NAFLD) remain to be fully elucidated. Ubiquitin specific protease 13 (USP13) is a critical participant in inflammation-related signaling pathways, which are linked to NAFLD. Herein, the roles of USP13 in NAFLD and the underlying mechanisms were investigated.
Methods: L02 cells and mouse primary hepatocytes were subjected to free fatty acid (FFA) to establish an in vitro model reflective of NAFLD. To prepare in vivo model of NAFLD, mice fed a high-fat diet (HFD) for 16 weeks and leptin-deficient (ob/ob) mice were used. USP13 overexpression and knockout (KO) strategies were employed to study the function of USP13 in NAFLD in mice.
Results: The expression of USP13 was markedly decreased in both in vitro and in vivo models of NAFLD. USP13 overexpression evidently inhibited lipid accumulation and inflammation in FFA-treated L02 cells in vitro. Consistently, the in vivo experiments showed that USP13 overexpression ameliorated hepatic steatosis and metabolic disorders in HFD-fed mice, while its deficiency led to contrary outcomes. Additionally, inflammation was similarly attenuated by USP13 overexpression and aggravated by its deficiency in HFD-fed mice. Notably, overexpressing of USP13 also markedly alleviated hepatic steatosis and inflammation in ob/ob mice. Mechanistically, USP13 bound to transforming growth factor β-activated kinase 1 (TAK1) and inhibited K63 ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways and promoting insulin signaling pathways. Inhibition of TAK1 activation reversed the exacerbation of NAFLD caused by USP13 deficiency in mice.
Conclusions: Our findings indicate the protective role of USP13 in NAFLD progression through its interaction with TAK1 and inhibition the ubiquitination and phosphorylation of TAK1. Targeting the USP13-TAK1 axis emerges as a promising therapeutic strategy for NAFLD treatment.
(© 2024. The Author(s).)

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82170827 National Natural Science Foundation of China; 82170829 National Natural Science Foundation of China; 82200639 National Natural Science Foundation of China; 21ZR1451200 Natural Science Foundation of Shanghai Municipality; 22ZR1450100 Natural Science Foundation of Shanghai Municipality

Keywords: Nonalcoholic fatty liver disease; Transforming growth factor beta-activated Kinase 1; Ubiquitin specific protease 13; Ubiquitination

EC 2.7.11.25 (MAP Kinase Kinase Kinases)
EC 3.4.19.12 (Ubiquitin-Specific Proteases)
EC 2.7.11.25 (MAP Kinase Kinase Kinase 7)
EC 3.4.19.12 (USP13 protein, human)

Date Created: 20240720 Date Completed: 20240720 Latest Revision: 20260127

20260130

PMC11264885

10.1186/s12967-024-05465-4

39033101