Carnitine palmitoyltransferase 1C: From cognition to cancer

Abstract

Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression.Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with L-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism.CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose-and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.

Fatty acid metabolism in CD8+ T cell memory: Challenging current concepts

“…CPT1B is expressed in heart, skeletal muscle, and testis; and CPT1C, the most recently characterized, is found primarily in brain, but has also been reported in tumor cell lines. [118][119][120][121] The reaction catalyzed by CPT1 is ratecontrolling for the oxidation of LCFAs and involves the conjugation of the long-chain acyl group to carnitine. The resulting long-chain acylcarnitines can then be transported through the mitochondrial inner membrane into the matrix by CACT and restored by CPT2…”

ROS homeostasis and metabolism: a critical liaison for cancer therapy

“…3, 71, 72 These approaches have led to the development of several molecules that are now entering clinical trials (Table 1), 2, 3, 5, 6, 12, 73, 74 and readers are referred to excellent reviews with detailed summaries of metabolic targets for cancer therapy. 5, 6 Proteins that are possible therapeutic targets include the glycolytic enzymes 6, 75 (hexokinase-2, 76 phosphoglycerate kinase-1, 77, 78 phosphoglycerate mutase, 79 PDK, 80 and PKM2, 36, 38 ) lipid synthesis/fatty acid metabolism targets (ATP citrate lyase, 81 fatty acid synthase, 82 monoglyceride lipase 83 and carnitine palmitoyltransferase 1(CPT1), 84 ) and the PPP proteins (glucose-6-phosphate dehydrogenase, 63 transaldolase and transketolase). 85 Several other glycolytic enzymes and transporters, including PFKFB3, 32 GAPDH, 86 LDH-A, 87 GLUT1 and GLUT4 88, 89 and monocarboxylate transporter 4 (MCT4), may become candidates for anticancer therapy.…”

DNA Methylation Biomarkers Of Myocardial Infarction And Cardiovascular Disease

“…Two previous candidate gene studies including both CpGs or cg21429551 alone have shown negative results regarding their association with CHD [32,36]. cg00574958, is located within CPT1A , which encodes an enzyme that regulates mitochondrial fatty acid oxidation [51]. It was positively associated with HDL-C levels and inversely associated with BMI and blood pressure, glucose and triglycerides levels.…”