CPT1A-mediated fat oxidation, mechanisms and therapeutic potential.

By Isabel R Schlaepfer, Molishree Joshi. Endocrinology, 2020

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Energy homeostasis during fasting or prolonged exercise depends on mitochondrial fatty acid oxidation (FAO). This pathway is crucial in many tissues with high energy demand and its disruption results in inborn FAO deficiencies. More than 15 FAO genetic defects have been currently described, and pathological variants described in circumpolar populations provide insights into its critical role in metabolism. The use of fatty acids as energy requires more than two dozen of enzymes and transport proteins, which are involved in the activation and transport of fatty acids into the mitochondria. As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and disease, including cancer. The CPT1 family of proteins contains three isoforms: CPT1A, CPT1B and CPT1C. This review focusses on CPT1A, the liver isoform that catalyzes the rate limiting step of converting acyl-CoA's into acyl-carnitines, which can then cross membranes to get into the mitochondria. The regulation of CPT1A is complex and has several layers that involve genetic, epigenetic, physiological and nutritional modulators. It is ubiquitously expressed in the body and associated with dire consequences linked with genetic mutations, metabolic disorders and cancers. This makes CPT1A an attractive target for therapeutic interventions. This review discusses our current understanding of CPT1A expression, its role in heath and disease and the potential for therapeutic opportunities targeting this enzyme.

Subfields: Cancer Research, Clinical Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/90d4a69f43e804b5267eaf950186a462fb0ddcbd