PMID- 19302064
OWN - NLM
STAT- MEDLINE
DCOM- 20090720
LR  - 20131121
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 420
IP  - 3
DP  - 2009 May 27
TI  - Modulation of the hepatic malonyl-CoA-carnitine palmitoyltransferase 1A 
      partnership creates a metabolic switch allowing oxidation of de novo fatty acids.
PG  - 429-38
LID - 10.1042/BJ20081932 [doi]
AB  - 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.
FAU - Akkaoui, Marie
AU  - Akkaoui M
AD  - Institut Cochin, Departement d'Endocrinologie, Metabolisme et Cancer, Universite 
      Paris Descartes, CNRS UMR 8104, Paris, France.
FAU - Cohen, Isabelle
AU  - Cohen I
FAU - Esnous, Catherine
AU  - Esnous C
FAU - Lenoir, Veronique
AU  - Lenoir V
FAU - Sournac, Martin
AU  - Sournac M
FAU - Girard, Jean
AU  - Girard J
FAU - Prip-Buus, Carina
AU  - Prip-Buus C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090527
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Fatty Acids)
RN  - 0 (Insulin)
RN  - 0 (Triglycerides)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Carnitine O-Palmitoyltransferase/genetics/*metabolism
MH  - Cells, Cultured
MH  - Fatty Acids/*metabolism
MH  - Fluorescent Antibody Technique
MH  - Genetic Vectors
MH  - Glucose/metabolism/pharmacology
MH  - Hepatocytes/cytology/drug effects/*metabolism
MH  - Immunoblotting
MH  - Insulin/pharmacology
MH  - Lipid Metabolism/drug effects
MH  - Liver/cytology/enzymology/metabolism
MH  - Male
MH  - Mitochondria/drug effects/metabolism
MH  - Models, Biological
MH  - Mutation
MH  - Oxidation-Reduction
MH  - Rats
MH  - Rats, Wistar
MH  - Transfection
MH  - Triglycerides/metabolism
EDAT- 2009/03/24 09:00
MHDA- 2009/07/21 09:00
CRDT- 2009/03/24 09:00
PHST- 2009/03/24 09:00 [entrez]
PHST- 2009/03/24 09:00 [pubmed]
PHST- 2009/07/21 09:00 [medline]
AID - BJ20081932 [pii]
AID - 10.1042/BJ20081932 [doi]
PST - epublish
SO  - Biochem J. 2009 May 27;420(3):429-38. doi: 10.1042/BJ20081932.