Insulin-like Growth Factor 1 Regulates the Expression of ATP-Binding Cassette Transporter A1 in Pancreatic Beta Cells

Abstract

ATP-binding cassette transporter A1 (ABCA1) in pancreatic beta cells influences insulin secretion and cholesterol homeostasis. The present study investigates whether insulin-like growth factor 1 (IGF-1), which mediates stimulation of ABCA1 gene expression, could also interfere with the phosphatidylinositol 3-kinase (PI3-K) cascade.

ABCA1 expression was examined by real-time polymerase chain reaction (PCR), Western blot analysis, and a reporter gene assay in rat insulin-secreting INS-1 cells incubated with IGF-1. The binding of forkhead box O1 (FoxO1) protein to the ABCA1 promoter was assessed by a chromatin immunoprecipitation (ChIP) assay. ABCA1 protein levels increased in response to rising concentrations of IGF-1. Real-time PCR analysis showed a significant increase in ABCA1 mRNA expression. However, both effects were suppressed after silencing the IGF-1 receptor. In parallel with its effect on endogenous ABCA1 mRNA levels, IGF-1 induced the activity of a reporter construct containing the ABCA1 promoter, while it was abrogated by LY294002, a specific inhibitor of PI3-K. Constitutively active Akt stimulated activity of the ABCA1 promoter, and a dominant-negative mutant of Akt or mutagenesis of the FoxO1 response element in the ABCA1 promoter abolished the ability of IGF-1 to stimulate promoter activity. A ChIP assay showed that FoxO1 mediated its transcriptional activity by directly binding to the ABCA1 promoter region. The knockdown of FoxO1 disrupted the effect of IGF-1 on ABCA1 expression. Furthermore, IGF-1 promoted cholesterol efflux and reduced the pancreatic lipotoxicity. These results demonstrate that the PI3-K/Akt/FoxO1 pathway contributes to the regulation of ABCA1 expression in response to IGF-1 stimulation.

Key words

ABCA1 - pancreatic beta cells - PI3K/Akt - FoxO1 - cholesterol efflux

• References

• 1 Brunham LR, Kruit JK, Verchere CB, Hayden MR. Cholesterol in islet dysfunction and type 2 diabetes. J Clin Invest 2008; 118: 403-408
• 2 Fielding CJ, Fielding PE. Molecular physiology of reverse cholesterol transport. J Lipid Res 1995; 36: 211-228
• 3 Brunham LR, Kruit JK, Pape TD, Timmins JM, Reuwer AQ, Vasanji Z, Marsh BJ, Rodrigues B, Johnson JD, Parks JS, Verchere CB, Hayden MR. Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med 2007; 13: 340-347
• 4 Blakesley VA, Butler AA, Koval AP, Okubo Y, LeRoith D. IGF-I receptor function: transducing the IGF-1 signal into intracellular events. In: The IGF System. Rosenfeld RG, Roberts JC. (eds.). Totowa: Humana Press; 1999: 143-163
• 5 Cheatham B, Kahn CR. Insulin action and the insulin signaling network. Endocr Rev 1995; 16: 117-142
• 6 Kulkarni RN, Holzenberger M, Shih DQ, Ozcan U, Stoffel M, Magnuson MA, Kahn CR. beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet 2002; 31: 111-115
• 7 Yoshida K, Murao K, Imachi H, Cao WM, Yu X, Li J, Ahmed RA, Kitanaka N, Wong NC, Unterman TG, Magnuson MA, Ishida T. Pancreatic glucokinase is activated by insulin-like growth factor-I. Endocrinology 2007; 148: 2904-2913
• 8 Ohtsuka S, Murao K, Imachi H, Cao WM, Yu X, Li J, Iwama H, Wong NC, Bancroft C, Ishida T. Prolactin regulatory element binding protein as a potential transcriptional factor for the insulin gene in response to glucose stimulation. Diabetologia 2006; 49: 1599-1607
• 9 Nishiuchi Y, Murao K, Imachi H, Nishiuchi T, Iwama H, Ishida T. Transcriptional factor prolactin regulatory element-binding protein-mediated gene transcription of ABCA1 via 3′,5′-cyclic adenosine-5′-monophosphate. Atherosclerosis 2010; 212: 418-425
• 10 Shahnaz B, Tada S, Kajikawa T, Ishida T, Kawanishi K. Automated fluorimetric determination of cellular cholesterol. Ann Clin Biochem 1998; 35 (Pt 5) 665-670
• 11 Lenzen S, Kloppel G. Insulin secretion and the morphological and metabolic characteristics of pancreatic islets of hyperthyroid ob/ob mice. Endocrinology 1978; 103: 1546-1555
• 12 Moses AC, Young SC, Morrow LA, O’Brien M, Clemmons DR. Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes. Diabetes 1996; 45: 91-100
• 13 Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96: 857-868
• 14 Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 2004; 117: 421-426
• 15 Oram JF, Vaughan AM. ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins. Curr Opin Lipidol 2000; 11: 253-260
• 16 Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest 1999; 104: R25-R31
• 17 Costet P, Luo Y, Wang N, Tall AR. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 2000; 275: 28240-28245
• 18 Engelking LJ, Kuriyama H, Hammer RE, Horton JD, Brown MS, Goldstein JL, Liang G. Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis. J Clin Invest 2004; 113: 1168-1175
• 19 Tamehiro N, Shigemoto-Mogami Y, Kakeya T, Okuhira K, Suzuki K, Sato R, Nagao T, Nishimaki-Mogami T. Sterol regulatory element-binding protein-2- and liver X receptor-driven dual promoter regulation of hepatic ABC transporter A1 gene expression: mechanism underlying the unique response to cellular cholesterol status. J Biol Chem 2007; 282: 21090-21099
• 20 Ohoka N, Okuhira K, Cui H, Wu W, Sato R, Naito M, Nishimaki-Mogami T. HNF4alpha increases liver-specific human ATP-binding cassette transporter A1 expression and cholesterol efflux to apolipoprotein A-I in response to cholesterol depletion. Arterioscler Thromb Vasc Biol 2012; 32: 1005-1014
• 21 Tang SL, Chen WJ, Yin K, Zhao GJ, Mo ZC, Lv YC, Ouyang XP, Yu XH, Kuang HJ, Jiang ZS, Fu YC, Tang CK. PAPP-A negatively regulates ABCA1, ABCG1 and SR-B1 expression by inhibiting LXRalpha through the IGF-I-mediated signaling pathway. Atherosclerosis 2012; 222: 344-354
• 22 de Haan W, Bhattacharjee A, Ruddle P, Kang MH, Hayden MR. ABCA1 in adipocytes regulates adipose tissue lipid content, glucose tolerance, and insulin sensitivity. J Lipid Res 2014; 55: 516-523
• 23 Li J, Murao K, Imachi H, Masugata H, Iwama H, Tada S, Zhang GX, Kobayashi R, Ishida T, Tokumitsu H. Exendin-4 regulates pancreatic ABCA1 transcription via CaMKK/CaMKIV pathway. J Cell Mol Med 2010; 14: 1083-1087
• 24 Miyai Y, Murao K, Imachi H, Li J, Nishiuchi Y, Masugata H, Iwama H, Kushida Y, Ishida T, Haba R. Exendin-4 regulates the expression of the ATP-binding cassette transporter A1 via transcriptional factor PREB in the pancreatic beta cell line. J Endocrinol Invest 2011; 34: e268-e274