Dietary fat and hepatic lipogenesis: the mitochondrial citrate carrier as a sensor of metabolic changes

The citrate carrier (CIC) is an integral protein of the inner mitochondrial membrane that has a fundamental role in hepatic intermediary metabolism. Its primary function is to catalyze the transport of citrate from mitochondria, where this molecule is formed, to cytosol, where this molecule is used for fatty acid and cholesterol synthesis. Therefore, mitochondrial CIC acts upstream of cytosolic lipogenic reactions and its regulation is particularly important in view of the modulation of hepatic lipogenesis. Whereas a great deal of data are currently available on the dietary modulation of cytosolic lipogenic enzymes, little is known about the nutritional regulation of the CIC transport activity. In this review we describe the differential effects of distinct fatty acids present in the diet on the activity of the mitochondrial CIC. In particular, polyunsaturated fatty acids were powerful modulators of the activity of mitochondrial CIC by influencing its expression through transcriptional and post-transcriptional mechanisms. On the contrary, saturated and monounsaturated fatty acids did not influence at all the mitochondrial CIC activity. Moreover, variations in the CIC activity were connected to similar alterations in the metabolic pathways to which the transported citrate is channelled. Therefore, CIC may be considered as a sensor for changes occurring inside the hepatocyte and may represent an important target for the regulation of hepatic lipogenesis. The crucial role of this protein is reinforced by the recent discovery of its involvement in other cellular processes, such as glucose-stimulated insulin secretion, inflammation, tumorigenesis, genome stability and sperm metabolism.