HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened

Abstract

Loss of pancreatic β-cell mass and function as a result of sustained ER stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of β-cells and insulin production involves hedgehog (Hh) signaling pathways as well as cholesterol-mediated effects. In fact, data from studies in humans and animal models suggest that HDL protects against the development of diabetes through inhibition of ER stress and β-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca2+-ATPase inhibitor, in β-cells of a rat insulinoma cell line, INS1e. We further explored effects on the Hh signaling receptor Smoothened (SMO) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced β-cell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (OHC). Supplementation of reconstituted HDL with 24-OHC enhanced and, in cells lacking ABCG1 or the 24-OHC synthesizing enzyme CYP46A1, restored the protective activity of HDL. Inhibition of SMO countered the beneficial effects of HDL and also LDL, and SMO agonists decreased β-cell apoptosis in the absence of ABCG1 or CYP46A1. The translocation of the SMO-activated transcription factor glioma-associated oncogene GLI-1 was inhibited by ER stress but restored by both HDL and 24-OHC. In conclusion, the protective effect of HDL to counter ER stress and β-cell death involves the transport, generation, and mobilization of oxysterols for activation of the Hh signaling receptor SMO Loss of pancreatic β-cell mass and function as a result of sustained ER stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of β-cells and insulin production involves hedgehog (Hh) signaling pathways as well as cholesterol-mediated effects. In fact, data from studies in humans and animal models suggest that HDL protects against the development of diabetes through inhibition of ER stress and β-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca2+-ATPase inhibitor, in β-cells of a rat insulinoma cell line, INS1e. We further explored effects on the Hh signaling receptor Smoothened (SMO) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced β-cell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (OHC). Supplementation of reconstituted HDL with 24-OHC enhanced and, in cells lacking ABCG1 or the 24-OHC synthesizing enzyme CYP46A1, restored the protective activity of HDL. Inhibition of SMO countered the beneficial effects of HDL and also LDL, and SMO agonists decreased β-cell apoptosis in the absence of ABCG1 or CYP46A1. The translocation of the SMO-activated transcription factor glioma-associated oncogene GLI-1 was inhibited by ER stress but restored by both HDL and 24-OHC. In conclusion, the protective effect of HDL to counter ER stress and β-cell death involves the transport, generation, and mobilization of oxysterols for activation of the Hh signaling receptor SMO Loss of pancreatic β-cell mass and function is the ultimate step in the pathogenesis of diabetes mellitus type 2 (1Cho J.H. Kim J.W. Shin J.A. Shin J. Yoon K.H. β-Cell mass in people with type 2 diabetes.J. Diabetes Investig. 2011; 2: 6-17Crossref PubMed Scopus (47) Google Scholar). Disturbed insulin secretion, high concentrations of glucose or FFAs, and other factors can lead to ER stress and, as the consequence, β-cell apoptosis (2Eizirik D.L. Cardozo A.K. Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus.Endocr. Rev. 2008; 29: 42-61Crossref PubMed Scopus (869) Google Scholar, 3Oyadomari S. Araki E. Mori M. Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells.Apoptosis. 2002; 7: 335-345Crossref PubMed Scopus (439) Google Scholar, 4Cnop M. Welsh N. Jonas J.C. Jorns A. Lenzen S. Eizirik D.L. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities.Diabetes. 2005; 54: S97-S107Crossref PubMed Scopus (1142) Google Scholar, 5Elouil H. Bensellam M. Guiot Y. Vander Mierde D. Pascal S.M. Schuit F.C. Jonas J.C. Acute nutrient regulation of the unfolded protein response and integrated stress response in cultured rat pancreatic islets.Diabetologia. 2007; 50: 1442-1452Crossref PubMed Scopus (120) Google Scholar). ER stress is a protective mechanism involving chaperones to assist refolding and degradation of unfolded proteins. In the case of sustained and extreme ER stress, the apoptotic mediator C/EBP homologous protein (CHOP) promotes cell death by decreasing B-cell lymphoma (Bcl)-2 expression (2Eizirik D.L. Cardozo A.K. Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus.Endocr. Rev. 2008; 29: 42-61Crossref PubMed Scopus (869) Google Scholar, 6Papa F.R. Endoplasmic reticulum stress, pancreatic beta-cell degeneration, and diabetes.Cold Spring Harb. Perspect. Med. 2012; 2: a007666Crossref PubMed Scopus (132) Google Scholar). HDLs promote the survival of different cell types. In pancreatic β-cells, HDL inhibits pro-apoptotic effects of native and oxidized LDLs, interleukin (IL)-1β, FFAs, tunicamycin, or thapsigargin (TG) (7von Eckardstein A. Widmann C. High-density lipoprotein, beta cells, and diabetes.Cardiovasc. Res. 2014; 103: 384-394Crossref PubMed Scopus (81) Google Scholar). The underlying mechanisms and receptors are unknown. However, they could help to explain the inverse association between plasma HDL-cholesterol and the risk of incident diabetes, which was observed in both epidemiological and genetic studies (8Holmes M.V. Ala-Korpela M. Smith G.D. Mendelian randomization in cardiometabolic disease: challenges in evaluating causality.Nat. Rev. Cardiol. 2017; 14: 577-590Crossref PubMed Scopus (231) Google Scholar, 9Li N. Fu J. Koonen D.P. Kuivenhoven J.A. Snieder H. Hofker M.H. Are hypertriglyceridemia and low HDL causal factors in the development of insulin resistance?.Atherosclerosis. 2014; 233: 130-138Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar) as well as the opposite modulation of glucose tolerance in genetic mouse models with HDL deficiency versus high HDL-cholesterol (10Parhofer K.G. Interaction between glucose and lipid metabolism: more than diabetic dyslipidemia.Diabetes Metab. J. 2015; 39: 353-362Crossref PubMed Scopus (185) Google Scholar). Cellular effects of HDL have been explained by two principal concepts. One model highlights direct and specific interactions between HDL-bound agonists and cellular receptors (11Annema W. von Eckardstein A. Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy.Transl. Res. 2016; 173: 30-57Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 12Nofer J.R. Signal transduction by HDL: agonists, receptors, and signaling cascades.Handb. Exp. Pharmacol. 2015; 224: 229-256Crossref PubMed Scopus (44) Google Scholar). The other model emphasizes the importance of HDL-induced cholesterol efflux via ABCA1 and ABCG1, which primarily alter cellular cholesterol homeostasis and, secondarily, cell function and survival (11Annema W. von Eckardstein A. Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy.Transl. Res. 2016; 173: 30-57Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 13Sorci-Thomas M.G. Thomas M.J. Microdomains, inflammation, and atherosclerosis.Circ. Res. 2016; 118: 679-691Crossref PubMed Scopus (107) Google Scholar). The quantity of cellular cholesterol determines the activity of transcription factors, such as SREBPs and LXRs (14Maxwell K.N. Soccio R.E. Duncan E.M. Sehayek E. Breslow J.L. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice.J. Lipid Res. 2003; 44: 2109-2119Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar). The crucial role of both SREBP2 and LXRs as well as their most prominent target genes, namely the LDL receptor and the mentioned ABC transporters, respectively, for β-cell function and hence glucose homeostasis have been demonstrated in β-cell-specific ABCA1 insulin secretion, glucose homeostasis and response to Med. 2007; PubMed Scopus Google Scholar, C. role for cholesterol in the of mouse pancreatic beta PubMed Scopus Google Scholar, N. C. W. A. D. of both ABCA1 and ABCG1 in in sterol inflammation, and beta-cell 2012; PubMed Scopus Google Scholar, W. efflux via and cholesterol via the LDL receptor of beta cell function in PubMed Scopus Google Scholar). in the of cholesterol also the activity of proteins. is the of the hedgehog (Hh) signaling Smoothened (SMO) and 1 on the of cholesterol between the and of the plasma SMO or is more Y. D.P. Y. A. W. Y. for cholesterol activity of the receptor Full Text Full Text PDF PubMed Scopus Google Scholar). Hh signaling role in development as well as regulation of insulin production and apoptosis of β-cells H. N. N. H. H. Y. effect of hedgehog signaling on in pancreatic 118: PubMed Scopus Google Scholar, E. S. C. J. D. role of signaling in pancreatic to J. 2016; 7: PubMed Google Scholar). In the to the mechanism by which native HDL as well as of such as which was to in diabetic A.K. Thomas N. glucose in with type 2 diabetes PubMed Scopus Google ER stress and apoptosis of pancreatic β-cells induced by which is a sarco/ER Ca2+-ATPase that ER The of in of from the endoplasmic Full Text PDF PubMed Scopus Google Scholar, J. J. J. M. Jonas J.C. Widmann C. HDLs pancreatic against ER stress by protein and 2012; PubMed Scopus Google Scholar). the rat insulinoma cell that the effect of HDL in β-cells involves the and efflux of specific oxysterols by and ABC transporters, respectively, and the activation of SMO by oxysterols to the translocation of glioma-associated oncogene a of the protein J. The mechanisms of and in development and Rev. 14: PubMed Scopus Google Scholar). pancreatic β-cell A. S. and in insulinoma PubMed Scopus Google and by C. D. N. C. modulation of insulin in cells to Pharmacol. PubMed Scopus Google cultured in with of and 1 and in a LDL and HDL from plasma of by as M.J. and of the lipoproteins and in the Lipid Res. Full Text PDF PubMed Google Scholar, C. S. W. von Eckardstein A. and of by PubMed Scopus Google Scholar). was from HDL by D. A. A. D. von Eckardstein A. of is for the of but through 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). of reconstituted HDLs by the of the M. C. M. D. von Eckardstein A. activation of and pathways by high-density from with coronary disease: role of high-density PubMed Scopus Google Scholar, S. A. M. J. von Eckardstein A. of high-density lipoproteins are with coronary and anti-apoptotic activity of 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). of and in a of with or the sterol of The or two different to and which the and of oxysterols in HDL. was different to which the in native HDL (10Parhofer K.G. Interaction between glucose and lipid metabolism: more than diabetic dyslipidemia.Diabetes Metab. J. 2015; 39: 353-362Crossref PubMed Scopus (185) Google Scholar) or the concentrations of oxysterols and was by of HDL plasma protein and from is the of for the of K.H. HDL for the of and 2016; PubMed Scopus Google Scholar, M. of reconstituted high-density lipoprotein, in with and from a 2015; PubMed Scopus Google Scholar). of was to in with diabetes A.K. Thomas N. glucose in with type 2 diabetes PubMed Scopus Google Scholar). Hh and by with was as the to target receptor and with as the and to target and control a of in to the The of was by or protein and expression as control and was on a was to and was the synthesis the as to cells in cells for the and in cells for the activity cultured for 2 and with and for and respectively, in the or absence of native or death was by with the and cell cells with and in and the of the cells with with and and in a 2. apoptotic cells as and and apoptotic cell as and cells for with and HDL or with 1 or or in the of for and oxysterols in both cells and The sterol and by was by but specific the and the oxysterols by specific and mass in the as in J. D. for the of sterol 2014; PubMed Scopus Google Scholar, D. N. S. N. J. M. and of and cholesterol in PubMed Scopus Google Scholar). cells in and cells cells on a and by the as in of 2 1 1 1 and and for on through a and on for The for The as with of and through a for and the was as a of protein on and in for the with or and on a with a of in the for 1 with in a of further with for 1 and for of ABCA1 ABCG1 and GLI-1 The or The data for the between was with for The data from in or are as was as We the of HDL to the apoptosis of cells as induced by that was to ER stress and apoptosis in mouse insulinoma cells and (7von Eckardstein A. Widmann C. High-density lipoprotein, beta cells, and diabetes.Cardiovasc. Res. 2014; 103: 384-394Crossref PubMed Scopus (81) Google Scholar, The of in of from the endoplasmic Full Text PDF PubMed Scopus Google Scholar). cells with of to ER apoptosis and with of native HDL for apoptosis was by inhibition was a of HDL The cells with or of for or in the or absence of native HDL or which plasma protein and which of HDL K.H. HDL for the of and 2016; PubMed Scopus Google Scholar) and which was to A.K. Thomas N. glucose in with type 2 diabetes PubMed Scopus Google Scholar). both HDL and the apoptosis of cells, of apoptosis was as or activity apoptosis HDL inhibited the of ER stress by different During as well as the expression of and HDL and abrogated but effect or effects on the expression of and the with cells, alter but the expression of and and effect was by both HDL and HDL and ER stress of We investigated the of cholesterol homeostasis to the protective effects of HDL. with the synthesis or the efflux of and as well as with of the was for for ABCA1 and ABCG1, and for the cells with for in the or absence of HDL or The of the enzyme of the cholesterol synthesis cell death and the anti-apoptotic of both HDL and the inhibition of cholesterol synthesis by the anti-apoptotic of HDL and of and but cell death and or the anti-apoptotic of HDL and the anti-apoptotic activity of HDL and on the and mobilization of cholesterol or specific and by cells in response to cells with for We and cell for the of by In both the and absence of the of and in cell and decreased the cellular in and 24-OHC However, cholesterol efflux the in the absence of Cellular and also by both in the and absence of In the of the of and in both cellular and that HDL efflux of oxysterols from cells ER We with oxysterols or cholesterol the anti-apoptotic of We the to of and in a of with or the sterol of The are in different which their concentrations in native HDL. of low of 24-OHC and anti-apoptotic The was observed for cholesterol of with and the anti-apoptotic activity of are from by of the or by cells 24-OHC cholesterol the cholesterol to and the cholesterol low We the on and of and was and the cells with for in the or absence of HDL or of and β-cell death The effect of native HDL was was to apoptosis but the data the importance of oxysterols, by the cells or with for the anti-apoptotic activity of HDL We investigated to with oxysterols can the of to β-cell death of cells in which and efflux by the of or for HDL and the of or the apoptotic effect of and decreased the anti-apoptotic effect of The of or cholesterol the anti-apoptotic activity of in the absence of or but to a in the absence of oxysterols can the LXR could the in cell death by of or of cells with LXR cell death or ER stress data that the anti-apoptotic activity of HDL the mobilization of specific oxysterols by ABCG1 or Hh signaling was to cells from cell death H. N. N. H. H. Y. effect of hedgehog signaling on in pancreatic 118: PubMed Scopus Google Scholar). cholesterol and oxysterols are to the activity of by the with inhibitor, or by direct activation Y. D.P. Y. A. W. Y. for cholesterol activity of the receptor Full Text Full Text PDF PubMed Scopus Google Scholar, D. M. C. Kim Y. J. A. Cellular cholesterol Smoothened in 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). investigated the of Hh signaling to the anti-apoptotic function of HDL. In a of Hh signaling with against and to The for for and for the cells with for or in the or absence of HDL or The anti-apoptotic effect of both native HDL and was by the with but by with or We further the of SMO to the anti-apoptotic activity of HDL by of cells with the SMO inhibitor, for abrogated the effects of both HDL and on the of of apoptosis as well as and of ER stress by in with SMO inhibition via or abrogated the effect of HDL on as by the or activation and on ER stress, as by SMO inhibition further β-cell death the and decreased apoptosis and and both and or β-cell death SMO by the translocation of the transcription factor GLI-1 from the of the the J. The mechanisms of and in development and Rev. 14: PubMed Scopus Google Scholar). We investigated to and oxysterols Hh cells with of and with native HDL or in the absence or of and for and and the with and decreased the of native HDL as well as with oxysterols but restored the of GLI-1 in the and oxysterols as well von Eckardstein A. and of and in 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, A. of oxidized oxysterols in the PubMed Scopus Google Scholar). to LDL anti-apoptotic effects in We the cells with HDL or LDL or LDL apoptosis as as HDL. The with LDL and HDL further the anti-apoptotic activity The of the two of HDL and LDL in are in of LDL more 24-OHC and more than HDL. investigated to the anti-apoptotic effect of LDL also on Hh SMO inhibition via or for and abrogated the effects of both HDL and We investigated the mechanism by which HDL protects pancreatic β-cells from ER stress and apoptosis. data from and or a complex mechanism that involves the and mobilization of oxysterols by specific and ABC transporters, respectively, and the activation of the Hh signaling receptor SMO the importance of cellular cholesterol homeostasis in β-cells for the control of glucose in and hence against with as well as low activity of the and genes to the risk of diabetes N. D. Welsh J.W. and risk of incident diabetes: a of Full Text Full Text PDF PubMed Scopus Google Scholar, D. Welsh of incident diabetes with with a 2011; PubMed Scopus Google Scholar, M.J. S. Smith S. in and and risk of and J. Med. 2016; PubMed Scopus Google Scholar). the of diabetes was to in with with their J. J.C. between and of type 2 diabetes 2015; PubMed Scopus Google Scholar). In the of or in pancreatic β-cells was to the of cellular cholesterol and of glucose tolerance ABCA1 insulin secretion, glucose homeostasis and response to Med. 2007; PubMed Scopus Google Scholar, C. role for cholesterol in the of mouse pancreatic beta PubMed Scopus Google Scholar, N. C. W. A. D. of both ABCA1 and ABCG1 in in sterol inflammation, and beta-cell 2012; PubMed Scopus Google Scholar, W. efflux via and cholesterol via the LDL receptor of beta cell function in PubMed Scopus Google Scholar). to β-cell namely insulin the activity of glucose and as well as by lipid and C. A. A. G.D. pancreatic beta-cell function and PubMed Scopus Google Scholar). data that of the or plasma with cholesterol also the survival of pancreatic β-cells J. D. for the of sterol 2014; PubMed Scopus Google Scholar). cholesterol in ER the of and ER stress and apoptosis J.H. The endoplasmic reticulum is in pancreatic beta-cell 2017; 7: PubMed Scopus Google Scholar). In cholesterol promotes the of and hence apoptosis C. K.N. M. N. M.J. The effect of cholesterol and by on of pancreatic control and In and in 2016; PubMed Scopus (57) Google Scholar, S. Y. Y. J. C. and apoptosis in mouse pancreatic beta-cell PubMed Scopus Google Scholar). In the plasma cholesterol the of which such as and stress, and lead to cellular apoptosis via of J. H. pancreatic beta cell apoptosis through stress 2011; PubMed Scopus (47) Google Scholar). In with the of that apoptosis of ABC and was by HDL-induced cholesterol efflux in or cells, the of or cholesterol efflux was to promote cell death E. J.L. ABCA1 and ABCG1 against apoptosis Res. PubMed Scopus Google Scholar, J. J. C. Y. A. ABCG1 deficiency promotes apoptosis by endoplasmic reticulum PubMed Scopus Google Scholar). However, in to a effect of in the inhibition of cholesterol synthesis by or with β-cell apoptosis and inhibited the anti-apoptotic function of HDL. in other cell was to apoptosis J. J. and cell apoptosis in cells via inhibition of the 39: PubMed Scopus Google Scholar, A. S. D. M. S. S. M. apoptosis in cells via PubMed Scopus Google Scholar, Y. J. Y. J. Y. W. inhibits cells by via Res. PubMed Scopus Google Scholar, J.H. Kim S. Kim J.H. Shin C/EBP homologous protein deficiency inhibits Res. PubMed Scopus Google Scholar). that the cellular or of cholesterol than cellular the survival of cells and other that HDL inhibits ER apoptosis of cells by and specific The with 24-OHC or apoptosis and the anti-apoptotic of HDL and more also in the absence of observed a in apoptosis of and the anti-apoptotic activity of was enhanced by with 24-OHC or In fact, oxysterols by HDL but also by LDL to anti-apoptotic to lipoproteins studies both and anti-apoptotic effects of 24-OHC N. Y. The genes, and pathways by in the of J. PubMed Scopus Google Scholar, Y. Y. M. Y. N. of on cell death and 2017; PubMed Scopus Google Scholar, Y. W. Y. N. of apoptosis and by is on activity of 2014; PubMed Scopus Google Scholar, A. Y. S. N. Y. Y. N. induced by through liver receptor cell 2: PubMed Scopus Google Scholar, M. effects of and 24-hydroxycholesterol against cell death in 2012; PubMed Scopus Google Scholar). the are to in concentrations or the of the in the cell the of or cholesterol the anti-apoptotic activity of more in the absence of ABCG1 than in the absence of of in the absence of oxysterols, was to the enhanced apoptosis of but of that of 24-OHC are more of apoptosis than 24-OHC are or or by and E. J. A. C. Y. and of oxysterols and in the mouse from and the PubMed Scopus Google Scholar). In of their anti-apoptotic is to that 24-OHC and but also or more by than cholesterol both in the or absence of with or ER stress In fact, cholesterol efflux the in the absence of the ER stress in cells, 24-OHC was to by HDL in J. J. C. Y. A. ABCG1 deficiency promotes apoptosis by endoplasmic reticulum PubMed Scopus Google Scholar). The have effect on apoptosis in efflux of 24-OHC from cells A. M. N. is from cells by PubMed Scopus Google Scholar). of ABCG1 a prominent of and in the J. J. and cell apoptosis in cells via inhibition of the 39: PubMed Scopus Google Scholar). In cells, oxysterols with the more than oxysterols with in the M. J. S. J.R. A. and in 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). are to through receptors, such as receptor and or receptors, such as or receptor from cholesterol to Lipid Res. 2016; PubMed Scopus Google Scholar). LXR the expression of ABC ABCA1 and ABCG1 C. receptors in lipid metabolism: for Rev. 2014; PubMed Scopus Google Scholar). with LXR anti-apoptotic activity in or inhibition of that anti-apoptotic of oxysterols are to LXR activation and of or We that oxysterols or by HDL target the Hh signaling receptor SMO to anti-apoptotic Hh signaling was to β-cells from by a mechanism that is by the or Hh and H. N. N. H. H. Y. effect of hedgehog signaling on in pancreatic 118: PubMed Scopus Google Scholar). that but or to apoptosis in ER cell the anti-apoptotic and ER of HDL abrogated by both with and inhibition of SMO with but by with or SMO agonists such as or apoptosis and cell death induced by or to of in with the of Hh signaling in the anti-apoptotic effects of the translocation of the transcription factor by the J.H. C. mechanisms of hedgehog PubMed Scopus Google Scholar) was decreased by ER stress but restored by both native HDL and with oxysterols the mechanism by which oxysterols or by lipoproteins SMO activity and ER apoptosis. In have been to Hh signaling by two mechanisms A. The of Smoothened and cholesterol in PubMed Scopus Google Scholar). the oxysterols the other of in the plasma was to crucial for the activity of SMO and or specific oxysterols such as and but and are for Hh signaling through SMO in cells hedgehog transduction and of 103: PubMed Scopus Google Scholar, J.R. N. M. are of the hedgehog signaling in 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Y. C. A. to the of Smoothened in PubMed Scopus Google Scholar). The effects of to and to with the S. J. are of the 2012; PubMed Scopus Google Scholar). The of on the cholesterol with oxysterols are on the cholesterol such as and are on the core of cholesterol hedgehog transduction and of 103: PubMed Scopus Google Scholar). In with in the with or the of to apoptosis In to direct of oxysterols to the of SMO S. C. and function of the Smoothened in 2: PubMed Google was also that cholesterol is of Hh a of SMO D. M. C. Kim Y. J. A. Cellular cholesterol Smoothened in 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). on the of cholesterol between the and of the plasma SMO or are more Y. D.P. Y. A. W. Y. for cholesterol activity of the receptor Full Text Full Text PDF PubMed Scopus Google Scholar). ABC including ABCA1 and ABCG1 are S. Smith translocation and cholesterol Full Text Full Text PDF PubMed Scopus Google that LDL, or ABC Hh signaling by the of cholesterol between the of the plasma However, explain the specific effects of 24-OHC and on ER stress and apoptosis. In conclusion, have a between sterol mobilization and Hh are by the of cell and a of ER stress and apoptosis. to mechanism is also of ER stress by more in cells and, in the crucial role of HDL in sterol efflux as well as the of Hh signaling and cellular such as the of other cellular of HDL modulation of Hh to diabetes, to of β-cells A. Y. stress and of pancreatic beta 2017; PubMed Scopus Google Scholar) is by HDL. We for with C/EBP homologous protein glioma-associated oncogene hedgehog hedgehog 1 reconstituted HDL Smoothened Smoothened receptor protein thapsigargin

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