Palmitate Inhibits Insulin Gene Expression by Altering PDX-1 Nuclear Localization and Reducing MafA Expression in Isolated Rat Islets of Langerhans

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2005 Jun 10

PMID 15944145

Citations 97

Authors

Derek K Hagman

Lori B Hays

Susan D Parazzoli

Vincent Poitout

Affiliations

Soon will be listed here.

Abstract

Abnormalities in lipid metabolism have been proposed as contributing factors to both defective insulin secretion from the pancreatic beta cell and peripheral insulin resistance in type 2 diabetes. Previously, we have shown that prolonged exposure of isolated rat islets of Langerhans to excessive fatty acid levels impairs insulin gene transcription. This study was designed to assess whether palmitate alters the expression and binding activity of the key regulatory factors pancreas-duodenum homeobox-1 (PDX-1), MafA, and Beta2, which respectively bind to the A3, C1, and E1 elements in the proximal region of the insulin promoter. Nuclear extracts of isolated rat islets cultured with 0.5 mm palmitate exhibited reduced binding activity to the A3 and C1 elements but not the E1 element. Palmitate did not affect the overall expression of PDX-1 but reduced its nuclear localization. In contrast, palmitate blocked the stimulation of MafA mRNA and protein expression by glucose. Combined adenovirus-mediated overexpression of PDX-1 and MafA in islets completely prevented the inhibition of insulin gene expression by palmitate. These results demonstrate that prolonged exposure of islets to palmitate inhibits insulin gene transcription by impairing nuclear localization of PDX-1 and cellular expression of MafA.

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References

Kelpe C, Moore P, Parazzoli S, Wicksteed B, Rhodes C, Poitout V . Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. J Biol Chem. 2003; 278(32):30015-21. DOI: 10.1074/jbc.M302548200. View

Samaras S, Zhao L, Means A, Henderson E, Matsuoka T, Stein R . The islet beta cell-enriched RIPE3b1/Maf transcription factor regulates pdx-1 expression. J Biol Chem. 2003; 278(14):12263-70. DOI: 10.1074/jbc.M210801200. View

Unger R . Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology. 2003; 144(12):5159-65. DOI: 10.1210/en.2003-0870. View

Olbrot M, Rud J, Moss L, Sharma A . Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc Natl Acad Sci U S A. 2002; 99(10):6737-42. PMC: 124472. DOI: 10.1073/pnas.102168499. View

Briaud I, Harmon J, Kelpe C, Segu V, Poitout V . Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes. 2001; 50(2):315-21. PMC: 3547289. DOI: 10.2337/diabetes.50.2.315. View

Jacqueminet S, Briaud I, Rouault C, Reach G, Poitout V . Inhibition of insulin gene expression by long-term exposure of pancreatic beta cells to palmitate is dependent on the presence of a stimulatory glucose concentration. Metabolism. 2000; 49(4):532-6. DOI: 10.1016/s0026-0495(00)80021-9. View

Campbell S, MacFarlane W . Regulation of the pdx1 gene promoter in pancreatic beta-cells. Biochem Biophys Res Commun. 2002; 299(2):277-84. DOI: 10.1016/s0006-291x(02)02633-5. View

Wu H, MacFarlane W, Tadayyon M, Arch J, James R, Docherty K . Insulin stimulates pancreatic-duodenal homoeobox factor-1 (PDX1) DNA-binding activity and insulin promoter activity in pancreatic beta cells. Biochem J. 1999; 344 Pt 3:813-8. PMC: 1220703. View

Melloul D, Ben-Neriah Y, Cerasi E . Glucose modulates the binding of an islet-specific factor to a conserved sequence within the rat I and the human insulin promoters. Proc Natl Acad Sci U S A. 1993; 90(9):3865-9. PMC: 46406. DOI: 10.1073/pnas.90.9.3865. View

10.

Matsuoka T, Zhao L, Artner I, Jarrett H, Friedman D, Means A . Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol Cell Biol. 2003; 23(17):6049-62. PMC: 180917. DOI: 10.1128/MCB.23.17.6049-6062.2003. View

11.

Gremlich S, Bonny C, Waeber G, Thorens B . Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J Biol Chem. 1997; 272(48):30261-9. DOI: 10.1074/jbc.272.48.30261. View

12.

MacFarlane W, McKinnon C, Cragg H, James R, Docherty K . Glucose stimulates translocation of the homeodomain transcription factor PDX1 from the cytoplasm to the nucleus in pancreatic beta-cells. J Biol Chem. 1999; 274(2):1011-6. DOI: 10.1074/jbc.274.2.1011. View

13.

Kharroubi I, Ladriere L, Cardozo A, Dogusan Z, Cnop M, Eizirik D . Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology. 2004; 145(11):5087-96. DOI: 10.1210/en.2004-0478. View

14.

Gerrish K, van Velkinburgh J, Stein R . Conserved transcriptional regulatory domains of the pdx-1 gene. Mol Endocrinol. 2004; 18(3):533-48. DOI: 10.1210/me.2003-0371. View

15.

Yoshikawa H, Tajiri Y, Sako Y, Hashimoto T, Umeda F, Nawata H . Effects of free fatty acids on beta-cell functions: a possible involvement of peroxisome proliferator-activated receptors alpha or pancreatic/duodenal homeobox. Metabolism. 2001; 50(5):613-8. DOI: 10.1053/meta.2001.22565. View

16.

Marshak S, Benshushan E, SHOSHKES M, Havin L, Cerasi E, Melloul D . Functional conservation of regulatory elements in the pdx-1 gene: PDX-1 and hepatocyte nuclear factor 3beta transcription factors mediate beta-cell-specific expression. Mol Cell Biol. 2000; 20(20):7583-90. PMC: 86312. DOI: 10.1128/MCB.20.20.7583-7590.2000. View

17.

MacFarlane W, Shepherd R, Cosgrove K, James R, Dunne M, Docherty K . Glucose modulation of insulin mRNA levels is dependent on transcription factor PDX-1 and occurs independently of changes in intracellular Ca2+. Diabetes. 2000; 49(3):418-23. DOI: 10.2337/diabetes.49.3.418. View

18.

Elks M . Chronic perifusion of rat islets with palmitate suppresses glucose-stimulated insulin release. Endocrinology. 1993; 133(1):208-14. DOI: 10.1210/endo.133.1.8319569. View

19.

MacFarlane W, Smith S, James R, Clifton A, Doza Y, Cohen P . The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic beta-cells. J Biol Chem. 1997; 272(33):20936-44. DOI: 10.1074/jbc.272.33.20936. View

20.

Petersen H, Peshavaria M, Pedersen A, Philippe J, Stein R, Madsen O . Glucose stimulates the activation domain potential of the PDX-1 homeodomain transcription factor. FEBS Lett. 1998; 431(3):362-6. DOI: 10.1016/s0014-5793(98)00776-5. View