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J. Biol. Chem., Vol. 280, Issue 37, 32413-32418, September 16, 2005

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

Derek K. Hagman, Lori B. Hays, Susan D. Parazzoli, and Vincent Poitout¶1

From the Pacific Northwest Research Institute, Seattle, Washington 98122 and the Department of Medicine, University of Washington, Seattle, Washington 98195

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.

Received for publication, June 2, 2005

^* This work was supported by National Institutes of Health Grant R01DK58096 and by the 2003 Thomas R. Lee career development award from the American Diabetes Association (to V. P.).

¹ To whom correspondence should be addressed: Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122. Tel.: 206-860-6755; Fax: 206-726-1217; E-mail: vpoitout{at}pnri.org.

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