GIPC1 Regulates The Expression And Function Of High-density Lipoprotein Receptor SR-BI

In recent years,the incidence of cardiovascular disease caused by metabolic abnormalities such as hypercholesterolemia has been increasing year by year in China,its pathogenesis has been a focus of biomedical research for a long time.Scavenger receptor class B type I(SR-B?)plays a key role in cholesterol transport metabolism,and it is able to uptake high-density lipoprotein cholesterol esters(HDL-CE)into cells selectively.Thus,SR-B? removes plasma cholesterol through the Cholesterol Reverse Transport(RCT).In RCT progress,Under the action of cholesterol ester transfer protein,high-density lipoprotein(HDL)converts excess cholesterol absorbed from peripheral tissues into cholesteryl ester(CE),then liver and steroidogenic tissues can uptake CE selectively which mediated by SR-B?.At last,it is excreted in the form of bile,bile acids or steroid hormones.Therefore,Regulating the expression of SR-B? in cells plays an important role in preventing the deposition of cholesterol on the arterial wall and transporting cholesterol from the blood vessel wall into the liver for metabolism.SR-B? is regulated by different expression levels of cells such as transcription and post-transcription.It has been reported that,hormones such as Adrenocorticotropic hormone(ACTH)can regulate the transcription of SR-B?.Many members of the PDZ protein family can regulate the expression of SR-B?,among which PDZK1(PDZ domain containing 1)is one of the earliest discovered proteins that combined with SR-B?,it can regulate the expression of SR-B? and affect the selective uptake of cholesteryl ester from plasma.Earlier studies in our laboratory also found that the other two PDZ family members,NHERF1 and NHERF2,which can regulate SR-B? expression by affecting the translation and protein degradation of SR-B?.In the present study,we identified a new protein interacting with SR-B? by mass spectrometry.It found that is a member of the PDZ family,GIPC1(GAIP interacting protein,C-terminus 1).We confirmed that GIPC1 binds to the intracellular domain of SR-B? through the PDZ domain.Co-transfected GIPC1 can significantly increase the expression of SR-B? in cells,and it was found that the PDZ domain and N-terminal GH1 domain of GIPC1 play an important role in the regulation of SR-B? protein expression,and also reported that SR-B? can be degraded by the ubiquitin-proteasome pathway.In our study,we found that the proteasome inhibitor MG 132 can inhibit the up-regulation of SR-B? protein expression by GIPC1,and it can down-regulate the ubiquitination of SR-B?.GIPC1 express in different tissues,and has a higher expression in tissues that SR-B? highly expressed.In the liver tissues of obese mice with high-fat diet and obob knockout,the protein expression levels of GIPC1 and SR-B? both decreased.In mouse liver cells,the expression of SR-B? can be regulated by overexpression and interference of GIPC1,which lead to the selective uptake of CE and the content of triglyceride(TG)and lipid.These results suggest that GIPC1 can regulate the expression of SR-B?,thus affecting cholesterol transport metabolism.These results indicated that the present study enriched the molecular mechanism of SR-B? expression and cholesterol transport regulation,providing a theoretical basis and potential intervention targets for the treatment of hypercholesterolemia cardiovascular diseases.