Modulation of the hepatic malonyl-CoA-carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids.
Liver mitochondrial beta-oxidation of LCFAs (long-chain fatty acids) is tightly regulated through inhibition of CPT1A (carnitine palmitoyltransferase 1A) by malonyl-CoA, an intermediate of lipogenesis stimulated by glucose and insulin. Moreover, CPT1A sensitivity to malonyl-CoA inhibition varies markedly depending on the physiopathological state of the animal. In the present study, we asked whether an increase in CPT1A activity solely or in association with a decreased malonyl-CoA sensitivity could, even in the presence of high glucose and insulin concentrations, maintain a sustained LCFA beta-oxidation and/or protect from triacylglycerol (triglyceride) accumulation in hepatocytes. We have shown that adenovirus-mediated expression of rat CPT1wt (wild-type CPT1A) and malonyl-CoA-insensitive CPT1mt (CPT1AM593S mutant) in cultured fed rat hepatocytes counteracted the inhibition of oleate beta-oxidation induced by 20 mM glucose/10 nM insulin. Interestingly, the glucose/insulin-induced cellular triacylglycerol accumulation was prevented, both in the presence and absence of exogenous oleate. This resulted from the generation of a metabolic switch allowing beta-oxidation of de novo synthesized LCFAs, which occurred without alteration in glucose oxidation and glycogen synthesis. Moreover, CPT1mt expression was more effective than CPT1wt overexpression to counteract glucose/insulin effects, demonstrating that control of CPT1A activity by malonyl-CoA is an essential driving force for hepatic LCFA metabolic fate. In conclusion, the present study highlights that CPT1A is a prime target to increase hepatic LCFA beta-oxidation and that acting directly on the degree of its malonyl-CoA sensitivity may be a relevant strategy to prevent and/or correct hepatic steatosis.
Akkaoui
Marie
M
Institut Cochin, Département d'Endocrinologie, Métabolisme et Cancer, Université Paris Descartes, CNRS UMR 8104, Paris, France.
Cohen
Isabelle
I
Esnous
Catherine
C
Lenoir
Véronique
V
Sournac
Martin
M
Girard
Jean
J
Prip-Buus
Carina
C
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
D005227:Fatty Acids; D007328:Insulin; D014280:Triglycerides; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose