FATTY-ACIDS DECREASE IDX-1 EXPRESSION IN RAT PANCREATIC-ISLETS AND REDUCE GLUT2, GLUCOKINASE, INSULIN, AND SOMATOSTATIN LEVELS

IDX-1 (islet/duodenum homeobox-1) is a transcription factor expressed in the duodenum and pancreatic beta and delta cells, It is required fo r embryonic development of the pancreas and transactivates the Glut2, glucokinase, insulin, and somatostatin genes, Here we show that exposu re of isolated rat pancreatic islets to palmitic acid induced a simila r to 70% decrease in IDX-1 mRNA and protein expression as well as 40 a nd 65% decreases in the binding activity of IDX-1 for its cognate cis- regulatory elements of the Glut2 and insulin promoters, respectively, The inhibitory effect of palmitic acid required its mitochondrial oxid ation since it was prevented by the carnitine palmitoyltransferase I i nhibitor bromopalmitic acid, The palmitic acid effect on IDX-1 was cor related with decreases in GLUT2 and glucokinase expression of 40 and 2 5%, respectively, at both the mRNA and protein levels, Insulin and som atostatin mRNA expression was also decreased by 40 and 60%, whereas gl ucagon mRNA expression was not modified, After 48 h of exposure to fat ty acids, total islet insulin, somatostatin, and glucagon contents wer e decreased by 85, 55, and 65%, respectively, At the same time, total hormone release was strongly stimulated (13-fold) for glucagon, wherea s its was only marginally increased for insulin and somatostatin (1.5- and 1.7-fold, respectively), These results indicate that elevated fat ty acid levels 1) negatively regulate Idx-1 expression; 2) decrease th e expression of genes transactivated by IDX-1 such as those for GLUT2, glucokinase, insulin, and somatostatin; and 3) lead to an important i ncrease in glucagon synthesis and secretion, Fatty acids thus have ple iotropic effects on pancreatic islet gene expression, and the negative control of Idx-1 expression may be an initial event in the developmen t of these multiple defects.