The adaptor protein GIPC1 stabilizes the scavenger receptor SR-B1 and increases its cholesterol uptake

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. 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. Scavenger receptor class B, type 1 (SR-B1) is an integral membrane glycoprotein that functions as a receptor for lipoproteins such as high-density lipoprotein (HDL) and low-density lipoprotein (LDL) (1Shen W.J. Azhar S. Kraemer F.B. SR-B1: A unique multifunctional receptor for cholesterol influx and efflux.Annu. Rev. Physiol. 2018; 80: 95-116Crossref PubMed Scopus (164) Google Scholar, 2Shen W.J. Asthana S. Kraemer F.B. Azhar S. Scavenger receptor B type 1: Expression, molecular regulation, and cholesterol transport function.J. Lipid Res. 2018; 59: 1114-1131Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). SR-B1 preferentially mediates selective uptake of HDL (and other lipoprotein)-derived cholesterol, cholesteryl esters (CEs), and unesterified cholesterol (UC), and it has also been shown that it facilitates free fatty acid (FFA) uptake in both primary adipocytes and model adipocyte cell lines (3Wang W. Yan Z. Hu J. Shen W.J. Azhar S. Kraemer F.B. Scavenger receptor class B, type 1 facilitates cellular fatty acid uptake.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2020; 1865: 158554Crossref PubMed Scopus (14) Google Scholar). SR-B1 plays an important role in the reverse cholesterol transport (RCT), a process by which excess cholesterol from peripheral tissues is transferred to the liver for metabolism and excretion into the bile and provides cholesterol substrate to the steroidogenic cells of the adrenal gland, ovary, and testis for steroid hormone production (2Shen W.J. Asthana S. Kraemer F.B. Azhar S. Scavenger receptor B type 1: Expression, molecular regulation, and cholesterol transport function.J. Lipid Res. 2018; 59: 1114-1131Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 4Shen W.J. Hu J. Hu Z. Kraemer F.B. Azhar S. Scavenger receptor class B type I (SR-BI): A versatile receptor with multiple functions and actions.Metabolism. 2014; 63: 875-886Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 5Hu Z. Shen W.J. Kraemer F.B. Azhar S. MicroRNAs 125a and 455 repress lipoprotein-supported steroidogenesis by targeting scavenger receptor class B type I in steroidogenic cells.Mol. Cell. Biol. 2012; 32: 5035-5045Crossref PubMed Scopus (101) Google Scholar). Given this, it is not surprising that SR-B1 is expressed at high levels in the liver and steroidogenic cells of the adrenal gland and ovary and testis (1Shen W.J. Azhar S. Kraemer F.B. SR-B1: A unique multifunctional receptor for cholesterol influx and efflux.Annu. Rev. Physiol. 2018; 80: 95-116Crossref PubMed Scopus (164) Google Scholar, 2Shen W.J. Asthana S. Kraemer F.B. Azhar S. Scavenger receptor B type 1: Expression, molecular regulation, and cholesterol transport function.J. Lipid Res. 2018; 59: 1114-1131Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Further studies demonstrated that SR-B1 participates in the uptake of several other molecules including vitamins, viruses (e.g., hepatitis C virus, dengue virus, SARS-CoV-2 [COVID-19]), plasmodium parasite, phagocytosis of apoptotic cells and identified as a receptor for silica with a potential role in silica-induced pulmonary inflammation in macrophage (4Shen W.J. Hu J. Hu Z. Kraemer F.B. Azhar S. Scavenger receptor class B type I (SR-BI): A versatile receptor with multiple functions and actions.Metabolism. 2014; 63: 875-886Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 6Westhaus S. Deest M. Nguyen A.T. Stanke F. Heckl D. Costa R. Schambach A. Manns M.P. Berg T. Vondran F.W. Sarrazin C. Ciesek S. von Hahn T. Scavenger receptor class B member 1 (SCARB1) variants modulate hepatitis C virus replication cycle and viral load.J. Hepatol. 2017; 67: 237-245Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 7Tsugita M. Morimoto N. Tashiro M. Kinoshita K. Nakayama M. SR-B1 is a silica receptor that mediates canonical inflammasome activation.Cell Rep. 2017; 18: 1298-1311Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 8Langlois A.C. Manzoni G. Vincensini L. Coppee R. Marinach C. Guerin M. Huby T. Carriere V. Cosset F.L. Dreux M. Rubinstein E. Silvie O. Molecular determinants of SR-B1-dependent Plasmodium sporozoite entry into hepatocytes.Sci. Rep. 2020; 10: 13509Crossref PubMed Scopus (8) Google Scholar, 9Wei C. Wan L. Yan Q. Wang X. Zhang J. Yang X. Zhang Y. Fan C. Li D. Deng Y. Sun J. Gong J. Yang X. Wang Y. Wang X. et al.HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry.Nat. Metab. 2020; 2: 1391-1400Crossref PubMed Scopus (130) Google Scholar). SR-B1 is also implicated in tumor aggressiveness and in the prognosis of breast cancer (10Gutierrez-Pajares J.L. Ben Hassen C. Chevalier S. Frank P.G. SR-BI: Linking cholesterol and lipoprotein metabolism with breast and prostate cancer.Front. Pharmacol. 2016; 7: 338Crossref PubMed Scopus (49) Google Scholar, 11Rajora M.A. Zheng G. Targeting SR-BI for cancer diagnostics, imaging and therapy.Front. Pharmacol. 2016; 7: 326Crossref PubMed Scopus (29) Google Scholar). In both rodent and human steroidogenic tissues, the expression of steroidogenic SR-B1 is subject to transcriptional regulation by tissue-specific tropic hormones (e.g., adrenal, ACTH, ovary, LH/FSH, and Leydig cells of testis, LH) via several transcription factors such as SF-1, LXRα and LXRβ, Sp1, PPARα, SREBP-1a, LRH-1, ERα and ERβ, CREB and NR0B1/DAX-1 (1Shen W.J. Azhar S. Kraemer F.B. SR-B1: A unique multifunctional receptor for cholesterol influx and efflux.Annu. Rev. Physiol. 2018; 80: 95-116Crossref PubMed Scopus (164) Google Scholar, 12Mizutani T. Yamada K. Minegishi T. Miyamoto K. Transcriptional regulation of rat scavenger receptor class B type I gene.J. Biol. Chem. 2000; 275: 22512-22519Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 13Lu X. He L.F. Zhou Q. Wang M.N. Shen W.J. Azhar S. Pan F.Y. Guo Z.G. Hu Z.G. NHERF1 and NHERF2 regulation of SR-B1 stability via ubiquitination and proteasome degradation.Biochem. Biophys. Res. Commun. 2017; 490: 1168-1175Crossref PubMed Scopus (5) Google Scholar). Our previous study demonstrated that DNA methylation status of SR-B1 promoter is also regulated by tropic hormone or its second messenger, cAMP, and participates in the regulation of SR-B1 expression in steroid-producing cells (14Hu Z.G. Li J.X. Kuang Z.H. Wang M. Azhar S. Guo Z.G. Cell-specific polymorphism and hormonal regulation of DNA methylation in scavenger receptor class B, type I.DNA Cell Biol. 2016; 35: 280-289Crossref PubMed Scopus (6) Google Scholar). Likewise, many dietary manipulations, hormones, and pharmacological agents transcriptionally regulate hepatic SR-B1 (4Shen W.J. Hu J. Hu Z. Kraemer F.B. Azhar S. Scavenger receptor class B type I (SR-BI): A versatile receptor with multiple functions and actions.Metabolism. 2014; 63: 875-886Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 15Trigatti B.L. Krieger M. Rigotti A. Influence of the HDL receptor SR-BI on lipoprotein metabolism and atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1732-1738Crossref PubMed Scopus (211) Google Scholar, 16Kent A.P. Stylianou I.M. Scavenger receptor class B member 1 protein: Hepatic regulation and its effects on lipids, reverse cholesterol transport, and atherosclerosis.Hepat. Med. 2011; 3: 29-44PubMed Google Scholar). Both hepatic and steroidogenic SR-B1s are also subject to posttranscriptional and posttranslational regulation. The scaffold protein PDZK1/NHERF3 is a regulator of hepatic SR-B1; it interacts with and helps to maintain expression, cell surface and selective transport function in O. Krieger M. of the protein in the HDL receptor PubMed Scopus Google Scholar, B.L. SR-B1 and in HDL 2017; PubMed Scopus (21) Google Scholar). In PDZK1/NHERF3 is not in steroidogenic cells and not regulate steroidogenic other NHERF1 and with both hepatic and steroidogenic SR-B1s and regulate expression and function by degradation via (1Shen W.J. Azhar S. Kraemer F.B. SR-B1: A unique multifunctional receptor for cholesterol influx and efflux.Annu. Rev. Physiol. 2018; 80: 95-116Crossref PubMed Scopus (164) Google Scholar, 13Lu X. He L.F. Zhou Q. Wang M.N. Shen W.J. Azhar S. Pan F.Y. Guo Z.G. Hu Z.G. NHERF1 and NHERF2 regulation of SR-B1 stability via ubiquitination and proteasome degradation.Biochem. Biophys. Res. Commun. 2017; 490: 1168-1175Crossref PubMed Scopus (5) Google Scholar, Z.G. Hu J. Zhang Z.H. Shen W.J. Kraemer F.B. Azhar S. of expression and function of scavenger receptor class B, type I by regulatory factors Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). we that and steroid hormone production and of SR-B1 expression by to of SR-B1 in steroidogenic cells Z. Shen W.J. Kraemer F.B. Azhar S. MicroRNAs 125a and 455 repress lipoprotein-supported steroidogenesis by targeting scavenger receptor class B type I in steroidogenic cells.Mol. Cell. Biol. 2012; 32: 5035-5045Crossref PubMed Scopus (101) Google Scholar). the expression of both in steroidogenic is by hormones and its second in increased expression and function of SR-B1 W.J. Azhar S. Kraemer F.B. regulation of adrenal 2016; 7: PubMed Scopus Google Scholar). and also regulate SR-B1 expression and function in the liver and L. Y. Yang F. MicroRNAs and repress selective high-density lipoprotein cholesterol uptake posttranscriptional Cell. Biol. PubMed Scopus Google Scholar, K. X. Zheng Z. Zhang by selective lipid uptake from HDL cholesterol via the of scavenger receptor class B type 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, M.N. Li R. Zhang W.J. Guo Z.G. Hu Z.G. of cholesterol uptake and lipid metabolism by targeting 2018; PubMed Scopus Google Scholar). We demonstrated that a 1 steroidogenesis by the and of SR-B1 Z.G. Hu J. Shen W.J. Kraemer F.B. Azhar S. A novel role of 1 in the regulation of scavenger receptor class B type 1 PubMed Scopus Google Scholar). In an to our the with the regulation of SR-B1 with a on the we SR-B1 and identified that a novel protein, can with the of SR-B1 and the expression, and the of the in protein C a protein, is a member of which also and M. J. Mol. Med. Google of GIPC1 type I to the J. Z. S. C. J. T. Li X. J. modulate PubMed Scopus Google Scholar). also at and The whereas the the of J. Z. S. C. J. T. Li X. J. modulate PubMed Scopus Google Scholar). GIPC1 is in of the versatile to with a of of which are or in and of Z. Z. Wang K. N. S. The role of the protein in receptor PubMed Scopus Google Scholar, M. human and cancer of Mol. Med. PubMed Scopus Google Scholar, protein regulation of receptor and Pharmacol. PubMed Scopus Google Scholar). Our that GIPC1 interacts with hepatic its protein levels by SR-B1 protein and the selective HDL-cholesterol function of SR-B1 in Our a role for in the regulation of hepatic lipid metabolism and cholesterol the that with SR-B1 and regulate SR-B1 function in a of mouse SR-B1 was with mouse liver by with were by and were by the were to of the by identified GIPC1 as a of In we the of a hepatic SR-B1 protein also B.L. SR-B1 and in HDL 2017; PubMed Scopus (21) Google Scholar). of samples with demonstrated that interacts with endogenous GIPC1 in liver and liver endogenous GIPC1 or cell from GIPC1 overexpressing cells the interaction between SR-B1 and GIPC1 including GIPC1 an 1 a and a M. human and cancer of Mol. Med. PubMed Scopus Google Scholar). which of are for GIPC1 targeting to we a of constructs of GIPC1 and expressed in a human cell and that was for with SR-B1 In GIPC1 constructs or effect on GIPC1 targeting to The SR-B1 was also and with GIPC1 into cells for of or of SR-B1 effect on its to with GIPC1 We and that and can with SR-B1 and regulate its protein levels and modulate selective transport function in model cell lines X. He L.F. Zhou Q. Wang M.N. Shen W.J. Azhar S. Pan F.Y. Guo Z.G. Hu Z.G. NHERF1 and NHERF2 regulation of SR-B1 stability via ubiquitination and proteasome degradation.Biochem. Biophys. Res. Commun. 2017; 490: 1168-1175Crossref PubMed Scopus (5) Google Scholar, O. Krieger M. of the protein in the HDL receptor PubMed Scopus Google Scholar, Z.G. Hu J. Zhang Z.H. Shen W.J. Kraemer F.B. Azhar S. of expression and function of scavenger receptor class B, type I by regulatory factors Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Given and the that GIPC1 can regulate cellular protein levels by with the and cellular or degradation S. role for the in regulation of degradation and J. PubMed Scopus Google Scholar, T. S. D. R. J. G. A protein interacts with the of the receptor not with the Biol. Chem. Full Text Full Text PDF PubMed Scopus Google we GIPC1 interaction with SR-B1 its expression cells were with SR-B1 ± GIPC1 of cellular demonstrated that of GIPC1 was associated with expression of SR-B1 protein levels in cellular from SR-B1 and GIPC1 cells is SR-B1 in and the of SR-B1 in cell is to its physiological in 1 to whereas the of GIPC1 is to its physiological in cells not We the effect of on the selective transport function of in that of GIPC1 to of uptake We the of GIPC1 on the expression of of SR-B1 Overexpression of GIPC1 the expression of SR-B1 constructs and with the of These are in with the shown in In to wild-type constructs or were in to the expression of SR-B1 Our previous studies demonstrated that the protein levels of SR-B1 were in a of cellular protein X. He L.F. Zhou Q. Wang M.N. Shen W.J. Azhar S. Pan F.Y. Guo Z.G. Hu Z.G. NHERF1 and NHERF2 regulation of SR-B1 stability via ubiquitination and proteasome degradation.Biochem. Biophys. Res. Commun. 2017; 490: 1168-1175Crossref PubMed Scopus (5) Google Scholar). we the GIPC1 SR-B1 protein levels by SR-B1 protein cells were with SR-B1 ± GIPC1 constructs for and cells were with levels were at by These demonstrated that of GIPC1 stabilizes cellular SR-B1 protein levels and we to protein degradation function is by the and in to increased SR-B1 protein 1 to cells and mouse primary cells were with lysosomal or the of the with the Both and SR-B1 protein levels in 1 to cells, whereas effect on SR-B1 expression were primary mouse The of SR-B1 with GIPC1 in cells or of SR-B1 cells with cells the SR-B1 protein effect on the SR-B1 protein expression also SR-B1 protein levels in SR-B1 overexpressing cells and the SR-B1 protein levels in cells SR-B1 and These that GIPC1 SR-B1 protein levels by the protein stability via the negative regulation of proteasomal and lysosomal protein degradation pathways. We GIPC1 is in the regulation of hepatic SR-B1 expression and lipid metabolism in a mouse cell and primary mouse Overexpression of GIPC1 SR-B1 protein levels in the SR-B1 levels We the effect of increased expression of GIPC1 on uptake in cells with In cells the uptake of was increased as with cells. We also the effect of increased expression of in cellular lipid lipid shown in cells overexpressing GIPC1 increased of In cellular TG and TC levels were also increased in GIPC1 1 to cells and mouse primary and the protein in lipid and cholesterol metabolism that we by in to increased GIPC1 levels of were in GIPC1 cells the effect of GIPC1 on SR-B1 expression and lipid we GIPC1 expression in 1 to cells GIPC1 1 and and and metabolic The SR-B1 protein to and of for the cells with GIPC1 or we not a in the levels of SR-B1 in cells with GIPC1 A and of GIPC1 in 1 to cells also both uptake and lipid C and of cellular lipid that in to cells with the cells demonstrated lipid and TG and cholesterol levels, GIPC1 levels were by protein fatty cholesterol, and triglyceride including and were by GIPC1 expression, whereas that in fatty acid and that GIPC1 both the SR-B1 protein levels and cellular lipid uptake and We the effects of GIPC1 silencing of to on SR-B1 expression and lipid metabolism. The that of via to is in silencing the expression of endogenous hepatic GIPC1 we to hepatic SR-B1 protein GIPC1 silencing a of SR-B1 protein expression Likewise, hepatic TG and TC and hepatic high-density lipoprotein cholesterol and low-density lipoprotein cholesterol were with GIPC1 In plasma levels of TC, and were increased in the levels of SR-B1 in the liver samples from with The levels of and were in liver samples of GIPC1 as with and levels, however, These findings that GIPC1 regulation of hepatic SR-B1 and lipid metabolism is and between in in the interaction between GIPC1 and we studies liver samples from and at the of to the liver shown in a negative correlation was between levels and the of and the expression of was also correlated with the of and In GIPC1 and levels a positive on we studies mouse of the and shown in an to the protein levels of both GIPC1 and Likewise, protein levels of both GIPC1 and SR-B1 were attenuated in the liver samples of as with wild-type We that the protein, GIPC1 interacts with SR-B1 and is the of in GIPC1 expression by of GIPC1 or by SR-B1 expression, selective HDL-cholesterol transport and hepatic lipid metabolism. we that hepatic levels of both and are correlated with the of subjects. Likewise, hepatic protein levels of both GIPC1 and SR-B1 are in and our that protein, GIPC1 in to and PDZK1/NHERF3 plays a major regulatory role in the expression and function of hepatic an HDL receptor, is the lipoprotein receptor in high cholesterol tissues, such as the adrenal and (1Shen W.J. Azhar S. Kraemer F.B. SR-B1: A unique multifunctional receptor for cholesterol influx and efflux.Annu. Rev. Physiol. 2018; 80: 95-116Crossref PubMed Scopus (164) Google Scholar, 2Shen W.J. Asthana S. Kraemer F.B. Azhar S. Scavenger receptor B type 1: Expression, molecular regulation, and cholesterol transport function.J. Lipid Res. 2018; 59: 1114-1131Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). SR-B1 mediates the selective of cholesterol esters and cholesterol from HDL to the steroidogenic cells of the adrenal gland and for steroid hormone production (1Shen W.J. Azhar S. Kraemer F.B. SR-B1: A unique multifunctional receptor for cholesterol influx and efflux.Annu. Rev. Physiol. 2018; 80: 95-116Crossref PubMed Scopus (164) Google Scholar, A. Krieger M. The role of the high-density lipoprotein receptor SR-BI in the lipid metabolism of and other Rev. 2003; PubMed Scopus Google it also participates in reverse cholesterol transport and facilitates cellular fatty acid uptake (3Wang W. Yan Z. Hu J. Shen W.J. Azhar S. Kraemer F.B. Scavenger receptor class B, type 1 facilitates cellular fatty acid uptake.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2020; 1865: 158554Crossref PubMed Scopus (14) Google Scholar, M. HDL and reverse cholesterol Res. PubMed Scopus Google Scholar). The SR-B1 expression is subject to and posttranslational regulation X. He L.F. Zhou Q. Wang M.N. Shen W.J. Azhar S. Pan F.Y. Guo Z.G. Hu Z.G. NHERF1 and NHERF2 regulation of SR-B1 stability via ubiquitination and proteasome degradation.Biochem. Biophys. Res. Commun. 2017; 490: 1168-1175Crossref PubMed Scopus (5) Google Scholar). protein, is a major posttranslational regulator of hepatic SR-B1 not steroidogenic SR-B1; it is for the expression of hepatic SR-B1 its cell surface and selective HDL-cholesterol transport function of SR-B1 O. Krieger M. of the protein in the HDL receptor PubMed Scopus Google Scholar). In our previous studies identified other member of NHERF1 and that regulate expression and function of both steroidogenic and hepatic SR-B1s via of and increased degradation X. He L.F. Zhou Q. Wang M.N. Shen W.J. Azhar S. Pan F.Y. Guo Z.G. Hu Z.G. NHERF1 and NHERF2 regulation of SR-B1 stability via ubiquitination and proteasome degradation.Biochem. Biophys. Res. Commun. 2017; 490: 1168-1175Crossref PubMed Scopus (5) Google Scholar, Z.G. Hu J. Zhang Z.H. Shen W.J. Kraemer F.B. Azhar S. of expression and function of scavenger receptor class B, type I by regulatory factors Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with hepatic SR-B1 and posttranslational of SR-B1 at the protein NHERF1 and NHERF2 also negative functions steroidogenic GIPC1 is of versatile to with a of with a of metabolic and including cell surface receptor expression, of and at and Z. Z. Wang K. N. S. The role of the protein in receptor PubMed Scopus Google Scholar, M. human and cancer of Mol. Med. PubMed Scopus Google Scholar, protein regulation of receptor and Pharmacol. PubMed Scopus Google Scholar). has also been shown to with other including and GIPC1 is in receptor and by interaction with a of such as and M. human and cancer of Mol. Med. PubMed Scopus Google Scholar). The of GIPC1 mediates its whereas its protein The of GIPC1 can the of its M. human and cancer of Mol. Med. PubMed Scopus Google Scholar). Our studies suggest that GIPC1 its to to We also identified several including as the SR-B1-interacting by The studies demonstrated that of GIPC1 both endogenous and expression of SR-B1 protein These are with that GIPC1 is for and expression of such as and M. human and cancer of Mol. Med. PubMed Scopus Google Scholar, T. S. D. R. J. G. A protein interacts with the of the receptor not with the Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, X. T. A novel for of type receptor expression interaction with the protein, Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The studies in the interaction of protein, GIPC1 with functions to the SR-B1 protein expression and selective HDL-cholesterol transport in mouse liver cells. and demonstrated that GIPC1 cellular SR-B1 levels in both mouse model hepatic cell and primary The TG and TC levels were attenuated by of GIPC1 expression, whereas of GIPC1 cellular TG and TC in hepatic lipid including and were in to expression of of GIPC1 in mouse liver in was associated with increased levels of TG and TC, and hepatic TG and TC and of SR-B1 in human studies a negative correlation between hepatic GIPC1 expression and of subjects. In the expression of was correlated with the levels in human liver These findings are also in with the mouse of the and an to the protein levels of both GIPC1 and GIPC1 and SR-B1 protein levels were also attenuated in the of with wild-type suggest that GIPC1 of SR-B1 expression and function by which hepatic cells regulate lipid metabolism including cholesterol metabolism. stabilizes SR-B1 a whereas NHERF1 and NHERF2 regulate its protein levels by protein degradation via ubiquitination X. He L.F. Zhou Q. Wang M.N. Shen W.J. Azhar S. Pan F.Y. Guo Z.G. Hu Z.G. NHERF1 and NHERF2 regulation of SR-B1 stability via ubiquitination and proteasome degradation.Biochem. Biophys. Res. Commun. 2017; 490: 1168-1175Crossref PubMed Scopus (5) Google Scholar, O. Krieger M. of the protein in the HDL receptor PubMed Scopus Google Scholar, B.L. SR-B1 and in HDL 2017; PubMed Scopus (21) Google Scholar, A. O. Rigotti A. Krieger M. of high-density lipoprotein metabolism by the tissue-specific protein PubMed Scopus Google Scholar). that GIPC1 the SR-B1 protein levels, we to GIPC1 by the SR-B1 protein this, cells overexpressing SR-B1 and SR-B1 GIPC1 were with to the protein and cell samples and at were for SR-B1 protein levels by The of SR-B1 was increased in cells SR-B1 and GIPC1 as with cells overexpressing SR-B1 we that of hepatic cells with a proteasome or SR-B1 protein levels in 1 to cells, mouse primary and cells overexpressing SR-B1 and GIPC1 that SR-B1 protein degradation is by both proteasome and lysosomal pathways. expression of GIPC1 a elevated levels of SR-B1 protein in cells with or that GIPC1 regulation of SR-B1 also SR-B1 degradation via proteasome and lysosomal pathways. that SR-B1 protein, GIPC1 is for expression and function of SR-B1 and that SR-B1 and GIPC1 in to regulate hepatic cholesterol and lipid metabolism in and in at increased expression of SR-B1 regulation of hepatic cholesterol and lipid metabolism in the of the with including

Topics & Concepts