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

Abstract

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 (FA) 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. Although a great deal of data are currently available on the dietary modulation of cytosolic lipogenic enzymes, little is known about the nutritional regulation of CIC transport activity. In this review, we describe the differential effects of distinct FAs present in the diet on the activity of mitochondrial CIC. In particular, polyunsaturated FAs were powerful modulators of the activity of mitochondrial CIC by influencing its expression through transcriptional and posttranscriptional mechanisms. On the contrary, saturated and monounsaturated FAs did not influence mitochondrial CIC activity. Moreover, variations in CIC activity were connected to similar alterations in the metabolic pathways to which the transported citrate is channeled. 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.

FIGURE 1

Schematic representation of the secondary structure of the citrate carrier, which consists of 6 transmembrane helices (H1–H6), connected by 3 loops on the matrix side (M1–M3) and 2 loops on the intermembrane space (C1, C2). Matrix loops contain short amphipatic helices (h_1–2, h_3–4, and h_5–6). CS, carrier signature.

FIGURE 2

Schematic model depicting the key role of CIC in hepatic lipogenesis. CIC, citrate carrier; CL, ATP-citrate lyase; CS, citrate synthase; IDH, isocitrate dehydrogenase; MDH, malate dehydrogenase; ME, malic enzyme; NADH, reduced nicotinamide adenine dinucleotide hydrate; NAD⁺, oxidized nicotinamide adenine dinucleotide; OGC, oxoglutarate carrier; PC, pyruvate carboxylase; Pi, inorganic phosphate; PYC, pyruvate carrier.