Overexpression of Insig-1 Protects β Cell Against Glucolipotoxicity Via SREBP-1c

Overview

Journal J Biomed Sci

Publisher Biomed Central

Specialty Biology

Date 2011 Aug 17

PMID 21843373

Citations 15

Authors

Ke Chen

Ping Jin

Hong-Hui He

Yan-Hong Xie

Xiao-Yun Xie

Zhao-Hui Mo

Affiliations

Soon will be listed here.

Abstract

Background: High glucose induced lipid synthesis leads to β cell glucolipotoxicity. Sterol regulatory element binding protein-1c (SREBP-1c) is reported to be partially involved in this process. Insulin induced gene-1 (Insig-1) is an important upstream regulator of Insig-1-SREBPs cleavage activating protein (SCAP)-SREBP-1c pathway. Insig-1 effectively blocks the transcription of SREBP-1c, preventing the activation of the genes for lipid biosynthesis. In this study, we aimed to investigate whether Insig-1 protects β cells against glucolipotoxicity.

Methods: An Insig-1 stable cell line was generated by overexpression of Insig-1 in INS-1 cells. The expression of Insig-1 was evaluated by RT-PCR and Western blotting, then, cells were then treated with standard (11.2 mM) or high (25.0 mM) glucose for 0 h, 24 h and 72 h. Cell viability, apoptosis, glucose stimulated insulin secretion (GSIS), lipid metabolism and mRNA expression of insulin secretion relevant genes such as IRS-2, PDX-1, GLUT-2, Insulin and UCP-2 were evaluated.

Results: We found that Insig-1 suppressed the high glucose induced SREBP-1c mRNA and protein expression. Our results also showed that Insig-1 overexpression protected β cells from ER stress-induced apoptosis by regulating the proteins expressed in the IRE1α pathway, such as p-IRE1α, p-JNK, CHOP and BCL-2. In addition, Insig-1 up-regulated the expression of IRS-2, PDX-1, GLUT-2 and Insulin, down-regulated the expression of UCP-2 and improved glucose stimulated insulin secretion (GSIS). Finally, we found that Insig-1 inhibited the lipid accumulation and free fatty acid (FFA) synthesis in a time-dependent manner.

Conclusions: There results suggest that Insig-1 may play a critical role in protecting β cells against glucolipotoxicity by regulating the expression of SREBP-1c.

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References

Green H . Adipose conversion of 3T3 cells depends on a serum factor. Proc Natl Acad Sci U S A. 1978; 75(12):6107-9. PMC: 393127. DOI: 10.1073/pnas.75.12.6107. View

Prentki M, Joly E, El-Assaad W, Roduit R . Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes. 2002; 51 Suppl 3:S405-13. DOI: 10.2337/diabetes.51.2007.s405. View

Diraison F, Ravier M, Richards S, Smith R, Shimano H, Rutter G . SREBP1 is required for the induction by glucose of pancreatic beta-cell genes involved in glucose sensing. J Lipid Res. 2008; 49(4):814-22. PMC: 6101217. DOI: 10.1194/jlr.M700533-JLR200. View

Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E . Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest. 2002; 109(4):525-32. PMC: 150879. DOI: 10.1172/JCI14550. View

Sandberg M, Fridriksson J, Madsen L, Rishi V, Vinson C, Holmsen H . Glucose-induced lipogenesis in pancreatic beta-cells is dependent on SREBP-1. Mol Cell Endocrinol. 2005; 240(1-2):94-106. DOI: 10.1016/j.mce.2005.05.005. View

Engelking L, Kuriyama H, Hammer R, Horton J, Brown M, Goldstein J . Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis. J Clin Invest. 2004; 113(8):1168-75. PMC: 385408. DOI: 10.1172/JCI20978. View

Eizirik D, Cardozo A, Cnop M . The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2007; 29(1):42-61. DOI: 10.1210/er.2007-0015. View

Takahashi A, Motomura K, Kato T, Yoshikawa T, Nakagawa Y, Yahagi N . Transgenic mice overexpressing nuclear SREBP-1c in pancreatic beta-cells. Diabetes. 2005; 54(2):492-9. DOI: 10.2337/diabetes.54.2.492. View

McPherson R, Gauthier A . Molecular regulation of SREBP function: the Insig-SCAP connection and isoform-specific modulation of lipid synthesis. Biochem Cell Biol. 2004; 82(1):201-11. DOI: 10.1139/o03-090. View

10.

Im S, Kang S, Kim S, Kim H, Kim J, Kim K . Glucose-stimulated upregulation of GLUT2 gene is mediated by sterol response element-binding protein-1c in the hepatocytes. Diabetes. 2005; 54(6):1684-91. DOI: 10.2337/diabetes.54.6.1684. View

11.

Yang T, Espenshade P, Wright M, Yabe D, Gong Y, Aebersold R . Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell. 2002; 110(4):489-500. DOI: 10.1016/s0092-8674(02)00872-3. View

12.

Li J, Takaishi K, Cook W, McCorkle S, Unger R . Insig-1 "brakes" lipogenesis in adipocytes and inhibits differentiation of preadipocytes. Proc Natl Acad Sci U S A. 2003; 100(16):9476-81. PMC: 170943. DOI: 10.1073/pnas.1133426100. View

13.

Yamashita T, Eto K, Okazaki Y, Yamashita S, Yamauchi T, Sekine N . Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a beta-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c. Endocrinology. 2004; 145(8):3566-77. DOI: 10.1210/en.2003-1602. View

14.

Maedler K, Oberholzer J, Bucher P, Spinas G, Donath M . Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes. 2003; 52(3):726-33. DOI: 10.2337/diabetes.52.3.726. View

15.

Solinas G, Naugler W, Galimi F, Lee M, Karin M . Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci U S A. 2006; 103(44):16454-9. PMC: 1637603. DOI: 10.1073/pnas.0607626103. View

16.

Poitout V, Amyot J, Semache M, Zarrouki B, Hagman D, Fontes G . Glucolipotoxicity of the pancreatic beta cell. Biochim Biophys Acta. 2009; 1801(3):289-98. PMC: 2824006. DOI: 10.1016/j.bbalip.2009.08.006. View

17.

Ruderman N, Prentki M . AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov. 2004; 3(4):340-51. DOI: 10.1038/nrd1344. View

18.

Dong X, Tang S . Insulin-induced gene: a new regulator in lipid metabolism. Peptides. 2010; 31(11):2145-50. DOI: 10.1016/j.peptides.2010.07.020. View

19.

Unger R, Zhou Y . Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes. 2001; 50 Suppl 1:S118-21. DOI: 10.2337/diabetes.50.2007.s118. View

20.

Bernal-Mizrachi E, Wen W, Stahlhut S, Welling C, Permutt M . Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J Clin Invest. 2001; 108(11):1631-8. PMC: 200992. DOI: 10.1172/JCI13785. View