Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells

In pancreatic β cells, ABCA1, a 254 kDa membrane protein, affects cholesterol homeostasis and insulin secretion. Angiotensin II, as the main effector of the renin–angiotensin system, decreases glucose-stimulated insulin secretion (GSIS). We examined the effect of angiotensin II on ABCA1 expression in primary pancreatic islets and INS-1 cells. Angiotensin II decreased ABCA1 protein and mRNA; angiotensin II type 1 receptor (AT1R) blockade rescued this ABCA1 repression. In parallel, angiotensin II suppressed the promoter activity of ABCA1, an effect that was abrogated by PD98095, a specific inhibitor of MAPK kinase (MEK). LXR enhanced ABCA1 promoter activity, and angiotensin II decreased the nuclear abundance of LXR protein. On a chromatin immunoprecipitation assay, LXR mediated the transcription of ABCA1 by directly binding to its promoter. Mutation of the LXR binding site on the ABCA1 promoter cancelled the effect of angiotensin II. Furthermore, angiotensin II induced cholesterol accumulation and impaired GSIS; inhibition of AT1R or MEK pathway reversed these effects. In summary, our study showed that angiotensin II suppressed ABCA1 expression in pancreatic islets and INS-1 cells, indicating that angiotensin II may influence GSIS by regulating ABCA1 expression. Additional research may address therapeutic needs in diseases such as diabetes mellitus. In pancreatic β cells, ABCA1, a 254 kDa membrane protein, affects cholesterol homeostasis and insulin secretion. Angiotensin II, as the main effector of the renin–angiotensin system, decreases glucose-stimulated insulin secretion (GSIS). We examined the effect of angiotensin II on ABCA1 expression in primary pancreatic islets and INS-1 cells. Angiotensin II decreased ABCA1 protein and mRNA; angiotensin II type 1 receptor (AT1R) blockade rescued this ABCA1 repression. In parallel, angiotensin II suppressed the promoter activity of ABCA1, an effect that was abrogated by PD98095, a specific inhibitor of MAPK kinase (MEK). LXR enhanced ABCA1 promoter activity, and angiotensin II decreased the nuclear abundance of LXR protein. On a chromatin immunoprecipitation assay, LXR mediated the transcription of ABCA1 by directly binding to its promoter. Mutation of the LXR binding site on the ABCA1 promoter cancelled the effect of angiotensin II. Furthermore, angiotensin II induced cholesterol accumulation and impaired GSIS; inhibition of AT1R or MEK pathway reversed these effects. In summary, our study showed that angiotensin II suppressed ABCA1 expression in pancreatic islets and INS-1 cells, indicating that angiotensin II may influence GSIS by regulating ABCA1 expression. Additional research may address therapeutic needs in diseases such as diabetes mellitus. In pancreatic β cells, lipotoxicity induced by cholesterol accumulation results in the apoptosis of β cells and impaired insulin secretion (1.Zhou Y.P. Grill V. Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans.J. Clin. Endocrinol. Metab. 1995; 80: 1584-1590Crossref PubMed Google Scholar, 2.Unger R.H. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications.Diabetes. 1995; 44: 863-870Crossref PubMed Google Scholar). ABCA1 is a 254 kDa protein in membrane and serves as a key regulator in lipid exporting from cytoplasm to apolipoproteins and reverse cholesterol transport in vivo (3.Fielding C.J. Fielding P.E. Molecular physiology of reverse cholesterol transport.J. Lipid Res. 1995; 36: 211-228Abstract Full Text PDF PubMed Google Scholar). Previously, it was reported that specific inactivation of the ABCA1 gene in β cells induced glucose intolerance and defective insulin secretion in mice, but normal insulin sensitivity was retained (4.Brunham L.R. Kruit J.K. Pape T.D. Timmins J.M. Reuwer A.Q. Vasanji Z. Marsh B.J. Rodrigues B. Johnson J.D. Parks J.S. et al.Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.Nat. Med. 2007; 13: 340-347Crossref PubMed Scopus (337) Google Scholar). Absence of ABCA1 in pancreatic islets altered cholesterol homeostasis and impaired glucose-stimulated insulin secretion (GSIS) in vitro, suggesting that cholesterol accumulation may result in dysfunction of β cells in T2D (5.Brunham L.R. Kruit J.K. Verchere C.B. Hayden M.R. Cholesterol in islet dysfunction and type 2 diabetes.J. Clin. Invest. 2008; 118: 403-408Crossref PubMed Scopus (126) Google Scholar). Angiotensin II (Ang II) is the central effector of the renin–angiotensin system (RAS) and is known to regulate vascular tone, blood pressure, and electrolyte homeostasis (6.Touyz R.M. Schiffrin E.L. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells.Pharmacol. Rev. 2000; 52: 639-672PubMed Google Scholar). Ang II type 1 (AT1) and type 2 (AT2) receptors are the main receptors involved in mediating Ang II's effect (7.de Gasparo M. Catt K.J. Inagami T. Wright J.W. Unger T. International union of pharmacology. XXIII. The angiotensin II receptors.Pharmacol. Rev. 2000; 52: 415-472PubMed Google Scholar). A previous study showed that Ang II significantly enhanced cholesterol accumulation by suppressing ABCA1 expression in macrophages (8.Yang H.Y. Bian Y.F. Xiao C.S. Liang B. Zhang N. Gao F. Yang Z.M. Angiotensin-(1–7) stimulates cholesterol efflux from angiotensin II-treated cholesterol-loaded THP-1 macrophages through the suppression of p38 and c-Jun N-terminal kinase signaling.Mol. Med. Rep. 2015; 12: 1387-1392Crossref PubMed Scopus (7) Google Scholar), indicating the role of Ang II in the regulation of cholesterol homeostasis. Recently, in vivo Ang II has been reported to be able to dose-dependently induce blood vessel contraction and decrease glucose-dependent insulin secretion in pancreatic islets; these effects are altered by inhibition of the AT1 receptor (AT1R) (9.Ihoriya C. Satoh M. Kuwabara A. Sasaki T. Kashihara N. Angiotensin II regulates islet microcirculation and insulin secretion in mice.Microcirculation. 2014; 21: 112-123Crossref PubMed Scopus (13) Google Scholar, 10.Lau T. Carlsson P.O. Leung P.S. Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets.Diabetologia. 2004; 47: 240-248Crossref PubMed Scopus (201) Google Scholar). Interestingly, several recent large-scale clinical studies reported that, compared with other antihypertensive drugs or placebo, antagonists of angiotensin receptor or inhibitors of angiotensin-converting enzyme remarkably reduced the incidence of T2D in hypertensive patients (11.Jandeleit-Dahm K.A. Tikellis C. Reid C.M. Johnston C.I. Cooper M.E. Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes.J. Hypertens. 2005; 23: 463-473Crossref PubMed Scopus (266) Google Scholar). This evidence suggests the important role of Ang II in regulation of pancreatic islet function. However, the detailed mechanism in the inhibition of insulin secretion by Ang II is not completely understood. In this study, we hypothesized that Ang II might increase the cholesterol accumulation by decreasing ABCA1 expression and then induce lipotoxicity in pancreatic β cells, thus attenuating insulin synthesis. The INS-1 is a cell line originally isolated from a rat insulinoma, which is developed and propagated at the Division of Biochimie Clinique (courtesy of C. B. Wollheim, Geneva, Switzerland). In this study, experiments were performed in cells during 9 ∼35 passages, and the cells were split every 7 days. These cells were cultured in RPMI 1640 medium (SIGAMA, Tokyo, Japan) containing 11.2 mmol/l glucose and supplemented with 10% heat-inactivated FBS (Dainippon Pharmaceutical Co., Ltd., Tokyo, Japan), 50 μmol/l 2-mercaptoethanol, 100 U/ml penicillin, and 100 μg/ml streptomycin. All cells were incubated in humidified 5% CO2 at 37°C. When 80% confluent, the cells were washed twice and incubated with 0.5% FBS RPMI 1640 medium for 6 h. Then, the cells were treated with varying doses of Ang II for 24 h before harvesting as described previously (12.Yu X. Murao K. Sayo Y. Imachi H. Cao W.M. Ohtsuka S. Niimi M. Tokumitsu H. Inuzuka H. Wong N.C. et al.The role of calcium/calmodulin-dependent protein kinase cascade in glucose upregulation of insulin gene expression.Diabetes. 2004; 53: 1475-1481Crossref PubMed Scopus (37) Google Scholar). Isolation of pancreatic islets from rat was performed as described previously (13.Li D.S. Yuan Y.H. Tu H.J. Liang Q.L. Dai L.J. A protocol for islet isolation from mouse pancreas.Nat. Protoc. 2009; 4: 1649-1652Crossref PubMed Scopus (245) Google Scholar). Briefly, the pancreas was digested by collagenase type V at 37°C for 15 min, and then islets were purified and collected by a 70 µm cell strainer. Finally, islets (100–200 µm) were picked and placed in RPMI 1640 medium supplemented with 10% heat-inactivated FBS, 100 U/ml penicillin, and 0.1 mg/ml streptomycin in a 5% CO2 incubator at 37°C. Isolated islets were used for experiments in 7 d. The 15–30 µg of proteins were separated by a 7.5% SDS-PAGE and transferred to PVDF membrane for immunoblotting. After blocking with 7.5% skim milk in PBS (pH 7.2) overnight at 4°C, the membrane was incubated with 0.1% Tween 20 in PBS (PBS-T) containing the receptor type 1 to to or MAPK or Signal overnight at 4°C, or to for 1 h at as described previously Y. Murao K. Imachi H. Y. H. H. Y. T. regulates the expression of the in the pancreatic cell Endocrinol. Invest. Google Scholar). was washed with for and then incubated for 1 h at with the to were washed for and were by was performed with a of 20 in The of the and reverse ABCA1 were and of as a and of the of were then to the and a of was with as described previously S. Murao K. Imachi H. Cao W.M. X. K. T. Wong N.C. et regulates ABCA1 expression in vascular smooth muscle PubMed Scopus Google Scholar). was used as the We used a containing the ABCA1 promoter and the gene as previously described Y. Murao K. Imachi H. T. H. T. gene transcription of ABCA1 Full Text Full Text PDF PubMed Scopus (13) Google Scholar). the of LXR ABCA1 was at and with a of showed and are by These that are for mediating effects of LXR its response and promoter was INS-1 cells were in medium containing Ang II for 24 h with or with 1 or to the kinase MAPK kinase p38 MAPK protein kinase A or protein kinase kinase pathway for X. Murao K. Imachi H. Cao W.M. K. T. Wong N.C. H. et of receptor gene expression by angiotensin II in vascular 2007; PubMed Scopus Google Scholar). the effect of blocking the cells were treated with Ang II with at varying and 100 for 24 h. Then, cells were and the promoter activity of ABCA1 was in an of the The were for the assay, which was performed to the Tokyo, immunoprecipitation was performed the to the was with 2 of LXR or was by to containing the LXR binding on rat ABCA1 promoter by and reverse as described previously M. K. et for in the regulation of ABCA1 and gene 23: PubMed Scopus Google Scholar). islets or INS-1 cells treated with varying were in containing and 0.1% (pH for 1 h. that, cells were incubated in containing glucose for 1 and then the medium was by supplemented with varying glucose with other After 1 h the was and used for insulin by and All the was performed in a 5% CO2 incubator at 37°C. The that were to LXR were as described previously C.S. of and of in 2009; Full Text Full Text PDF PubMed Scopus (126) Google Scholar). The that were to AT1R or were from or of the was performed as described previously Imachi H. H. Zhang H. Murao K. 1 regulates the expression of in pancreatic Metab. Res. PubMed Scopus Google Scholar). cholesterol we used a that used for the of cholesterol in with a as described previously Murao K. Imachi H. H. H. S. Zhang T. Tokumitsu H. regulates pancreatic ABCA1 transcription Med. Google Scholar). Briefly, INS-1 cells with varying were washed by PBS twice and with of A of of cell was treated with and used for cholesterol by The of cell was used for The cholesterol cell were by the of cholesterol to cell were as were by and A of was All experiments were performed at we isolated protein in INS-1 cells treated with Ang II at varying and used to the ABCA1 expression. We that Ang II remarkably decreased ABCA1 expression the expression of and in INS-1 cells. This was by the results of and Ang II at a of decreased the ABCA1 we used this of Ang II in the We the effect of Ang II at a of in rat pancreatic islets and that protein and expression of ABCA1 were decreased by the of Ang II study the effect of Ang II on ABCA1 gene we the that the promoter of ABCA1 INS-1 cells and treated these cells with Ang II at a of in Ang II decreased the promoter activity of we used several or to the or and that inhibition of the MEK pathway the effect of Ang II on ABCA1 promoter activity, suggesting that Ang II may regulate ABCA1 expression the MEK Furthermore, we treated INS-1 cells with Ang II for to the of the We that was a of MEK at Ang II and that was from and to the previous the the of ABCA1 protein induced by Ang II was MEK was by the expression of and ABCA1 is a cholesterol in the we then examined the effect of Ang II on cholesterol in INS-1 cells. by the Ang II at a of significantly the and of lipid in cholesterol showed that, the is µg cell in the with Ang II the cholesterol to of and inhibition of the MEK pathway by altered this A previous study that accumulation of cholesterol in pancreatic β cells in impaired insulin secretion (4.Brunham L.R. Kruit J.K. Pape T.D. Timmins J.M. Reuwer A.Q. Vasanji Z. Marsh B.J. Rodrigues B. Johnson J.D. Parks J.S. et al.Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.Nat. Med. 2007; 13: 340-347Crossref PubMed Scopus (337) Google Scholar). we the abundance of insulin in INS-1 cells treated with Ang II. in Ang II significantly decreased the of insulin in a dose-dependent that, GSIS showed that glucose insulin secretion to of and the increase of insulin secretion was INS-1 cells treated with Ang II were not able to release insulin response to glucose with the increase of insulin secretion in Ang II-treated cells was significantly However, this effect was MEK was by or AT1R was by results of GSIS were in primary pancreatic islets from rat These that Ang II decreased glucose-stimulated insulin release AT1R and the MEK pathway in pancreatic β cells. study that AT1R and the receptor are in INS-1 cells (7.de Gasparo M. Catt K.J. Inagami T. Wright J.W. Unger T. International union of pharmacology. XXIII. The angiotensin II receptors.Pharmacol. Rev. 2000; 52: 415-472PubMed Google Scholar). In our study, we that of the receptors were in INS-1 cells the mechanism in the of Ang II on ABCA1, we used the specific inhibitors to blockade receptor and that inhibition of AT1R by dose-dependently altered the effect of Ang II on the expression of ABCA1 and its promoter activity the expression of and In inhibition of the receptor by was not able to the of Ang II on ABCA1 promoter activity This result that Ang II regulates ABCA1 expression the we the effect of AT1R inhibitor on the of MEK and and that inhibition of AT1R of MEK and induced by Ang II at in inhibition of AT1R significantly cholesterol accumulation induced by Ang II, that Ang II functions the a we used to the expression of AT1R in INS-1 cells and that the effect of Ang II on the expression of ABCA1 not of AT1R the effect of Ang II on cholesterol accumulation in INS-1 cells. study that transcription LXR is able to ABCA1 transcription with the in macrophages Y. N. of the promoter by the 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In this study, we used to that LXR to the ABCA1 promoter in INS-1 cells of LXR and significantly enhanced ABCA1 promoter activity that LXR regulates ABCA1 transcription in INS-1 cells. the role of LXR in Ang ABCA1 we treated INS-1 cells with Ang II at for and that Ang II decreased the nuclear abundance of LXR protein influence of LXR expression suggesting that Ang II ABCA1 transcription through of LXR in the This was by the result that Ang II dose-dependently decreased the and nuclear protein of LXR in INS-1 cells inhibition of AT1R with the LXR expression compared with with Ang II suggesting that Ang II ABCA1 transcription transcription this we the site in the ABCA1 promoter and that Ang II AT1R inhibitor effect on this promoter activity of LXR the effects of Ang II and the AT1R inhibitor on the protein and expression of ABCA1 These are of the that Ang ABCA1 expression In the study, we that Ang II expression of ABCA1 in the pancreatic β cell line INS-1 and isolated rat A previous that GSIS was completely by of Ang II for in vivo (9.Ihoriya C. Satoh M. Kuwabara A. Sasaki T. Kashihara N. Angiotensin II regulates islet microcirculation and insulin secretion in mice.Microcirculation. 2014; 21: 112-123Crossref PubMed Scopus (13) Google Scholar). Ang II, the key effector of the mediated its effects binding to specific receptors on the cell pancreatic islet in the and of cell and and these functions are mediated the AT1R T. Carlsson P.O. Leung P.S. II type 1 receptor blockade and glucose in a mouse of type 2 PubMed Scopus Google Scholar). We that AT1R inhibitor the effect of Ang II on ABCA1 expression. We showed that Ang II GSIS by ABCA1 which may be mediated the of cholesterol in pancreatic in that and or in β cell insulin secretion response to glucose S. secretion and the and of pancreatic islets of PubMed Scopus Google Scholar). a of cholesterol in pancreatic islets and of insulin secretion are in β cell ABCA1 (4.Brunham L.R. Kruit J.K. Pape T.D. Timmins J.M. Reuwer A.Q. Vasanji Z. Marsh B.J. Rodrigues B. Johnson J.D. Parks J.S. et al.Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.Nat. Med. 2007; 13: 340-347Crossref PubMed Scopus (337) Google Scholar, L.R. Kruit J.K. Verchere C.B. Hayden M.R. Cholesterol in islet dysfunction and type 2 diabetes.J. Clin. Invest. 2008; 118: 403-408Crossref PubMed Scopus (126) Google Scholar), suggesting that cholesterol may directly the of β cells. In this study, we cholesterol and insulin secretion Ang II The important role of ABCA1 in glucose homeostasis was by the study that the expression of ABCA1 in β cells (4.Brunham L.R. Kruit J.K. Pape T.D. Timmins J.M. Reuwer A.Q. Vasanji Z. Marsh B.J. Rodrigues B. Johnson J.D. Parks J.S. et al.Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.Nat. Med. 2007; 13: 340-347Crossref PubMed Scopus (337) Google Scholar). In to this we previously that a of the 1 has a effect on ABCA1 expression pathway and which results in of insulin secretion Y. Murao K. Imachi H. Y. H. H. Y. T. regulates the expression of the in the pancreatic cell Endocrinol. Invest. Google Scholar, Murao K. Imachi H. H. H. S. Zhang T. Tokumitsu H. regulates pancreatic ABCA1 transcription Med. Google Scholar). These results that cholesterol pancreatic β cells from of the in this study was to study in by Ang II involved in ABCA1 gene which of the as as the LXR by a of with are a of protein that are to to a of and then to cell and B. Angiotensin II transduction and the protein kinase Res. 1995; PubMed Scopus Google Scholar). and are of and are by of and by MEK C.M. A. The primary of a protein kinase that the gene PubMed Scopus Google Scholar, are 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). studies that and are by with Ang II in vascular smooth muscle cells B. Angiotensin II transduction and the protein kinase Res. 1995; PubMed Scopus Google Scholar, Angiotensin II stimulates the and protein in cultured rat smooth muscle Res. PubMed Scopus Google and in pancreatic cells K. T. H. M. H. T. K. K. Angiotensin II kinase and through angiotensin II type receptor in human pancreatic 2004; Google Scholar). was that Ang II induced a key of by the of AT1R in pancreatic islets and β cells Y. of expression by angiotensin II in the pancreatic islets and 2007; PubMed Scopus Google Scholar). We examined this mechanism by a specific inhibitor of the and that Ang ABCA1 promoter activity through an mechanism These results that of by Ang II AT1R may to the role of in the of is a by in the ABCA1 The of in patients with to the accumulation of cholesterol in such as the and S. M. B. C. cholesterol efflux is a of role of the ABCA1 gene 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, it is reported that is ABCA1 in pancreatic β cells (4.Brunham L.R. Kruit J.K. Pape T.D. Timmins J.M. Reuwer A.Q. Vasanji Z. Marsh B.J. Rodrigues B. Johnson J.D. Parks J.S. et al.Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.Nat. Med. 2007; 13: 340-347Crossref PubMed Scopus (337) Google Scholar), suggesting that the of ABCA1 with lipid might result in the dysfunction of pancreatic β cells in patients with et reported that patients from T2D a significantly of the compared with by the glucose the that ABCA1 an important role in GSIS from β cells M. A. K. M. H. M. K. et insulin secretion in patients with ABCA1 2009; PubMed Scopus Google Scholar). In this study, the INS-1 cells with Ang ABCA1 were to a decreased insulin secretion in response to glucose in are in a of and is known that are able to regulate lipid homeostasis and cholesterol efflux from cells, and the cells from lipid and C. K. receptor in cholesterol Endocrinol. PubMed Scopus Google Scholar). binding to LXR response to the transcription of several and ABCA1 S. M. F. of in 2004; PubMed Scopus Google Scholar). A previous study that LXR is to to a site in the ABCA1 promoter and that this is to the upregulation of ABCA1 and cholesterol efflux Y. N. of the promoter by the 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). transcription such as protein protein and protein were to regulate the transcription of ABCA1 in THP-1 cells, cells, and primary mouse macrophages and cell line Y. V. C.J. F. et of gene in a effect of angiotensin Res. 2005; PubMed Google Scholar, N. S. M. N. M. F. S. gene transcription is by protein inhibits protein and of Res. 2007; PubMed Scopus Google Scholar, M. T. S. H. C. C. The protein is a of binding and gene expression and a of lipid Full Text Full Text PDF PubMed Scopus Google Scholar, N. Y. T. K. K. T. T. and promoter regulation of gene mechanism the response to cholesterol 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). Recently, et reported that a regulator in the of ABCA1 gene and cholesterol efflux H. M. H. N. A. H. et a regulator of ABCA1 cholesterol efflux and PubMed Scopus Google Scholar). The in the cholesterol in the upregulation of ABCA1 protein and which is to other cells with to cholesterol K. H.J. et regulates ABCA1, and expression by through the Full Text Full Text PDF PubMed Scopus Google Scholar, N. K. H. M. T. human expression and cholesterol efflux to in response to cholesterol PubMed Scopus Google Scholar). However, in pancreatic β cells, is known the mechanisms of ABCA1 gene expression. results that Ang II decreased ABCA1 promoter activity by the of LXR in the of the pancreatic cell which is with a recent study that inhibition of and of LXR in Y. Y. Yang X. M. X. Zhang X. et of and of LXR in 2015; PubMed Scopus Google Scholar). This study to the regulation of the ABCA1 gene by Ang II, suggesting that Ang ABCA1 expression might be to the lipotoxicity in pancreatic β cells, which may be a experiments be to the specific of ABCA1 by Ang II in pancreatic β cells a that cholesterol in INS-1 cells might be altered by Ang II results showed that Ang II cholesterol compared with the In the inhibitor Ang cholesterol studies that is a the of cholesterol in pancreatic islets and of insulin release in (4.Brunham L.R. Kruit J.K. Pape T.D. Timmins J.M. Reuwer A.Q. Vasanji Z. Marsh B.J. Rodrigues B. Johnson J.D. Parks J.S. et al.Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.Nat. Med. 2007; 13: 340-347Crossref PubMed Scopus (337) Google Scholar, A. Hayden M.R. ABCA1 in regulates lipid glucose and insulin Lipid Res. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar), suggesting that of cholesterol directly the of β cells. In our previous we that and insulin decrease the cholesterol in pancreatic β cells and ABCA1 expression the pathway or the cascade Y. Murao K. Imachi H. Y. H. H. Y. T. regulates the expression of the in the pancreatic cell Endocrinol. Invest. Google Scholar, Murao K. Imachi H. H. H. S. Zhang T. Tokumitsu H. regulates pancreatic ABCA1 transcription Med. Google Scholar), in enhanced insulin secretion. is that the an important role in the and In to the Ang II in the and it might specific functions by actions Y. of expression by angiotensin II in the pancreatic islets and 2007; PubMed Scopus Google Scholar). The from our study a role of the local pancreatic Ang II, and Ang II be as a therapeutic to pancreatic islets from lipotoxicity and dysfunction in In summary, our studies showed that Ang II suppressed the expression of ABCA1 the pathway and transcription LXR and then induced cholesterol accumulation in primary pancreatic islets of rat and INS-1 cells, in of These the that Ang II may the of pancreatic β cells by regulation of ABCA1 which may therapeutic in the of diabetes mellitus. The and for with angiotensin II angiotensin II type 1 angiotensin II type 2 angiotensin II type 1 receptor protein kinase kinase chromatin immunoprecipitation glucose-stimulated insulin secretion MAPK kinase kinase protein kinase A renin-angiotensin system receptor type 1

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