1. The adaptor protein GIPC1 stabilizes the scavenger receptor SR-B1 and increases its cholesterol uptake
- Author
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Rui Liu, Salman Azhar, Yan-Fu Qu, Qian Zhou, Ziyu Zhang, Zhigang Hu, Li Liu, Wen-Jun Shen, and Zhigang Guo
- Subjects
CD36 Antigens ,Male ,0301 basic medicine ,HFD, high-fat diet ,Very low-density lipoprotein ,IGF1R, insulin-like growth factor-1 receptor ,SIK1, salt inducible kinase 1 ,ERα, estrogen receptors α ,BMI, body mass index ,LH, luteinizing hormone ,Mice, Obese ,PFU, plaque-forming units ,Biochemistry ,SR-B1 ,LXRβ, liver X receptors β ,chemistry.chemical_compound ,PDZ protein GIPC1 ,SF-1, steroidogenic factor 1 ,Post-translational regulation ,Receptor ,Ad-sh, adenoviruses with GIPC1 shRNA ,Protein Stability ,Chemistry ,Cell biology ,Cholesterol ,Liver ,ERβ, estrogen receptors β ,LXRα, liver X receptors α ,CREB, cAMP response element binding protein ,ACTH, adrenocorticotropic hormone ,Ad-GFP, adenovirus-expressing green fluorescent proteins ,Dil, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate ,SR-B1, scavenger receptor class B type 1 ,Research Article ,NRP1, neuropilin 1 ,cholesterol uptake ,HDL, high-density lipoprotein ,SREBP-1a, sterol-regulatory element binding protein-1a ,GH1, GIPC homology 1 ,TG, Triglyceride ,CEs, cholesteryl esters ,03 medical and health sciences ,CHX, cycloheximide ,selective lipid transport ,Animals ,Humans ,TGFβR3, transforming growth factorβ receptor type Ⅲ ,oxLDL, oxidized LDL ,Scavenger receptor ,Molecular Biology ,Leu, leupeptin hemisulfate ,Adaptor Proteins, Signal Transducing ,Insulin-like growth factor 1 receptor ,PPARα, peroxisome proliferator–activated receptor α ,NR0B1 (DAX-1), nuclear receptor subfamily 0 group B member 1 ,030102 biochemistry & molecular biology ,HDL-C, HDL-cholesterol ,Liver receptor homolog-1 ,FA, fatty acid ,VLDL, very-low-density lipoprotein ,Biological Transport ,LDL-C, LDL-cholesterol ,Cell Biology ,Mice, Inbred C57BL ,TC, total cholesterol ,protein–protein interaction ,030104 developmental biology ,MS, mass spectrometry ,LRH-1, liver receptor homolog 1 ,FSH, follicle-stimulating hormone ,adaptor protein ,Lipoprotein - Abstract
The scavenger receptor class B type 1 (SR-B1), a high-density lipoprotein (HDL) receptor, is a membrane glycoprotein that mediates selective uptake of HDL-cholesterol and cholesterol ester (CE) into cells. SR-B1 is subject to posttranslational regulation; however, the underlying mechanisms still remain obscure. Here, we identified a novel SR-B1-interacting protein, GIPC1 (GAIP-interacting protein, C terminus 1) that interacts with SR-B1 and stabilizes SR-B1 by negative regulation of its proteasomal and lysosomal degradation pathways. The physiological interaction between SR-B1 and GIPC1 was supported by co-immunoprecipitation of wild-type and mutant GIPC1 constructs in SR-B1 ± GIPC1 overexpressing cells, in native liver cells, and in mouse liver tissues. Overexpression of GIPC1 increased endogenous SR-B1 protein levels, subsequently increasing selective HDL-cholesterol/CE uptake and cellular triglyceride (TG) and total cholesterol (TC) levels, whereas silencing of GIPC1 in the mouse liver was associated with blunted hepatic SR-B1 levels, elevated plasma TG and TC, and attenuated hepatic TG and TC content. A positive correlation was identified between GIPC1 and SR-B1 expression, and both expressions of GIPC1 and SR-B1 from human liver samples were inversely correlated with body mass index (BMI) from human subjects. We therefore conclude that GIPC1 plays a key role in the stability and function of SR-B1 and can also effectively regulate hepatic lipid and cholesterol metabolism. These findings expand our knowledge of the regulatory roles of GIPC1 and suggest that GIPC1 exerts a major effect on cell surface receptors such as SR-B1 and its associated hepatic lipid and cholesterol metabolic processes.
- Published
- 2021
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