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. 2022 May;75(5):1218-1234.
doi: 10.1002/hep.32179. Epub 2021 Dec 7.

OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways

Jie-Lei Zhang  1 , Bin-Bin Du  2 , Dian-Hong Zhang  2 , Huan Li  2 , Ling-Yao Kong  2 , Guang-Jian Fan  3 , Ya-Peng Li  2 , Peng-Cheng Li  2 , Cui Liang  2 , Zheng Wang  2 , Lu-Lu Yang  2 , Zheng-Yang Hao  2 , Lei-Ming Wu  2 , Zhen Huang  2 , Jian-Zeng Dong  2 , Jin-Ying Zhang  2 , Rui Yao  2 , Shou-Jun Wang  1 , Yan-Zhou Zhang  2
Affiliations

OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways

Jie-Lei Zhang et al. Hepatology. 2022 May.

Abstract

Background and aims: NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism-associated signaling pathways. However, the role of OTUB1 in NASH is unclarified.

Methods and results: We demonstrated that mice with Otub1 deficiency exhibited aggravated high-fat diet-induced and high-fat high-cholesterol (HFHC) diet-induced hyperinsulinemia and liver steatosis. Notably, hepatocyte-specific overexpression of Otub1 markedly alleviated HFHC diet-induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal-regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA-sequencing analysis and immunoblot analysis. Through immunoprecipitation-mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppressed its lysine 63-linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway.

Conclusions: OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6-mediated ASK1 activation. Targeting the OTUB1-TRAF6-ASK1 axis may be a promising therapeutic strategy for NASH.

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