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

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.

CCN6 improves hepatic steatosis, inflammation, and fibrosis in non‐alcoholic steatohepatitis

“…ASK1 is a mitogen‐activated protein kinase kinase kinase (MAP3K), and widely expressed in tissue and cells that regulates the MAPK pathways through homodimerization and subsequent autophosphorylation in response to stressful stimuli from various sources including ROS, endoplasmic reticulum stress, bacterial and viral infections, calcium inward flow, and inflammatory signals 33 . Numerous studies have demonstrated that overactivation of the ASK1/JNK/p38 pathway in the liver of NASH plays an important role in disease progression and that inhibition of ASK1 attenuates insulin resistance, inflammation and hepatic lipid accumulation in NASH 35–38 . Although some clinical trials on the treatment of NASH with small molecule inhibitors of ASK1 have not reached definitive endpoints yet, the current efforts of the researchers to treat NASH and its related complications by interfering with ASK1 have never been stopped 31,32 .…”

Osteoprotegerin deficiency aggravates methionine- choline- deficient diet-induced nonalcoholic steatohepatitis in mice

“…Three well-characterized MAPK subfamilies are p38, JNK, and ERK1/2, which are related to NASH development. MAPK can be activated by upstream kinase signals, such as apoptosis signal-regulated kinase 1 and mixed-spectrum kinase 3 31,32 . By contrast, MAPKs are inactivated through direct dephosphorylation of their threonine and tyrosine residues by a set of bispeci c protein tyrosines [33][34][35] .…”

TRAF6 Suppresses the Development of Pulmonary Fibrosis by Attenuating the Activation of Fibroblasts

“…TRAF6 contains a RING-finger domain in the N-terminus, which is responsible for its E3 ligase activity, followed by several zinc-finger domains and a conserved C-terminal TRAF domain that enables interaction with receptors and adaptor proteins. Recent studies have revealed the role of TRAF6 in fibrosis ( Wang et al, 2020 ; Zhang et al, 2021 ). TRAF6 overexpression in hepatocytes promotes ubiquitination-dependent activation of ASK1, contributing to the pathogenesis of hepatic fibrosis during the progression of nonalcoholic steatohepatitis (NASH) ( Wang et al, 2020 ).…”