GNAI2 Promotes The Progress Of NASH Via Combination With PRDX1

Non-alcoholic steatohepatitis（NASH）is the most dangerous factor leading to chronic liver diseases in western countries.Meanwhile,its morbidity is increasing dramatically in China these years.NASH is able to accelerate the progression to end-stage liver diseases,and contributes to the development of type 2 diabetes and cardiovascular diseases as independent risk factors.Although a large number of studies on the pathogenesis of NASH have been carried out in the past decade,due to its complex mechanism of pathogenesis,there is no reliable molecular marker in clinical diagnosis,so it can only be diagnosed by liver biopsy.At present,treatment for NASH is mainly diet and weight management,using some lipid-lowering,hypoglycemic,antioxidant and liver protecting drugs,lack of specific treatment drugs.Therefore,deeper investigation on pathophysiological mechanism of NASH is a desiderate task to provide brand-new theoretical basis for more efficient pharmaceutical research and clinical treatment mode.Guanine nucleotide–binding protein G alpha inhibiting activity polypeptide 2（GNAI2）,a subunit of heterotrimeric G protein,it participates in a variety of transcription regulation in cells,leading to a lot of pathological and physiological activities.Previous researches have shown that GNAI2 takes part in neurodegenerative diseases,inflammatory responses,immune deficiency and tumorigenesis.However,the role of GNAI2 in the pathogenesis of NASH has not been reported,and the underlying mechanism corelated to the pathogenesis of NASH remains to be uncovered.We found that protein and m RNA levels of GNAI2 in NASH specimens were dramatically higher than that in NAFLD and normal liver specimens.Besides,GNAI2expression was in positive connection with lipid deposition,inflammatory response and fibrosis levels in NASH,and correlated with autophagy level negatively.The same conclusion was reached in NASH models of WT mice,GNAI2^flox/floxmice and GNAI2^hep-/-mice as well as cell high fat models in vitro.Through further research,we found that GNAI2 could competitively combine with TRAF6 to Prdx1,so as to enhance the activity of TRAF6 ubiquitination ligase,increase the ubiquitination level of TRAF6and ECSIT,further activate the NF-κB pathway induced by TLR4,release inflammatory cytokines,trigger the inflammatory response in liver cells,and accelerate the progress of NASH.Overall,this study clarified the role of GNAI2 in promoting the development of NASH,and based on the regulation of GNAI2 on PRDX1,explored its molecular mechanism to promote the development of NASH.It is a new understanding of the signaling pathway network related to the development of NASH and offers a new idea for diagnosis and therapy of NASH in clinical practice.