Abstract
The transport of solutes across the inner mitochondrial membrane is catalyzed by a family of nuclear-encoded membrane-embedded proteins called mitochondrial carriers (MCs). The citrate carrier (CiC) and the carnitine/acylcarnitine transporter (CACT) are two members of the MCs family involved in fatty acid metabolism. By conveying acetyl-coenzyme A, in the form of citrate, from the mitochondria to the cytosol, CiC contributes to fatty acid and cholesterol synthesis; CACT allows fatty acid oxidation, transporting cytosolic fatty acids, in the form of acylcarnitines, into the mitochondrial matrix. Fatty acid synthesis and oxidation are inversely regulated so that when fatty acid synthesis is activated, the catabolism of fatty acids is turned-off. Malonyl-CoA, produced by acetyl-coenzyme A carboxylase, a key enzyme of cytosolic fatty acid synthesis, represents a regulator of both metabolic pathways. CiC and CACT activity and expression are regulated by different nutritional and hormonal conditions. Defects in the corresponding genes have been directly linked to various human diseases. This review will assess the current understanding of CiC and CACT regulation; underlining their roles in physio-pathological conditions. Emphasis will be placed on the molecular basis of the regulation of CiC and CACT associated with fatty acid metabolism.
Highlights
Mitochondria are well-defined cytoplasmic organelles, which undertake multiple critical functions in the cell
High levels of transcripts are found in liver, heart and skeletal muscle, where β-oxidation is essential for energy production; much lower levels are observed in other tissues, such as brain, placenta, kidney, pancreas and lung [16]
T3 stimulated in the liver the transcription of carnitine palmitoyl transferase 1 (CPT1) gene in coordination with other genes involved in fatty acid oxidation [39,40], binding to a thyroid hormone response element (TRE), present in CPT1 promoter [41]
Summary
Mitochondria are well-defined cytoplasmic organelles, which undertake multiple critical functions in the cell. High levels of transcripts are found in liver, heart and skeletal muscle, where β-oxidation is essential for energy production; much lower levels are observed in other tissues, such as brain, placenta, kidney, pancreas and lung [16] This carrier belongs to the carnitine palmitoyl transferase (CPT) system, the major site of control of fatty acid β-oxidation, which transports cytosolic long chain fatty acids (LCFA) in the form of esters of CoA-SH (LCFA-CoA) into the mitochondrial matrix for their oxidation [17]. In the fed state, when insulin/glucagon ratio is high, hepatic lipogenesis is active, the concentration of malonyl-CoA rises and becomes sufficient to inhibit CPT1 [19], the enzyme catalyzing the rate-limiting step in fatty acid oxidation. It follows that fatty acid oxidation and fatty acid synthesis fluctuate reciprocally with changes in malonyl-CoA levels [20]
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