Role of FOXA in mitochondrial citrate carrier gene expression and insulin secretion

The FOXA subfamily of forkhead box (FOX) transcription factors includes three members, FOXA1, FOXA2, and FOXA3 that play an important role in the control of glucose metabolism by regulating multiple target genes in liver, pancreas, and adipose tissue [1]. The mitochondrial citrate carrier (CIC), also known as the tricarboxylate carrier, is an integral protein of the mitochondrial inner membrane that is essential for fatty acid and sterol biosynthesis. Furthermore, CIC has been found to be involved in the control of glucose-stimulated insulin secretion [2]. CIC mRNA and/or protein levels are high in liver, pancreas and kidney. Recently, we have begun to investigate the transcriptional regulation mechanisms of CIC. In this study, we have investigated the transcriptional role of the FOXA site present in the promoter of the CIC gene. We have shown that wild-type CIC FOXA site confers transcriptional activation of the luciferase gene reporter, particularly in cells overexpressing FOXA1. We have also demonstrated that overexpression and silencing of FOXA increases and reduces CIC transcript and protein levels, respectively. In addition, FOXA1 silencing in INS-1 cells decreases not only CIC mRNA and protein but also the amount of citrate in the cytosol and glucose-stimulated insulin secretion. This finding is consistent with the recent report that FOXA1-deficient mouse islets exhibit a severe defect of glucose-stimulated insulin secretion [3]. On the basis of our results, the effect of FOXA1 on glucose-stimulated insulin secretion can be also explained by its transcriptional regulation of CIC gene expression. 1. J. Friedman, K. Kaestner, Cell. Mol. Life Sci. 63 (2006) 2317–2328 2. J. Joseph, M. Jensen, O. Ilkayeva, F. Palmieri, C. Alárcon, C. Rhodes, C. Newgard, J. Biol. Chem. 281 (2006) 35624–35632 3. M. Vatamaniuk, R. Gupta, K. Lantz, N. Doliba, F. Matschinsky, K. Kaestner, Diabetes 55 (2006) 2730–2736