Disease relevance of Cpt1a

• Human CPT1A deficiency is characterized by recurrent attacks of hypoketotic hypoglycemia [1].

High impact information on Cpt1a

• PXR directly bound to FoxA2 and repressed its activation of the Cpt1a and Hmgcs2 promoters [2].
• Treatment with PXR activator pregnenolone 16alpha-carbonitrile (PCN) down-regulated the mRNA levels of carnitine palmitoyltransferase 1A (in beta-oxidation) and mitochondrial 3-hydroxy-3-methylglutarate-CoA synthase 2 (in ketogenesis) in wild-type (Pxr(+/+)) mice only [2].
• Instead, genes of fatty acid oxidation such as Cpt-1 (carnitine palmitoyltransferase-1) as well as Pgc-1alpha are induced [3].
• The results provide direct support for the hypothesis that the malonyl-CoA/CPTI interaction is a component of a metabolic signaling network that controls insulin secretion [4].
• CPT-I converts long-chain fatty acyl-CoAs to acylcarnitines for translocation across the mitochondrial membrane [5].

Biological context of Cpt1a

• We predict that this region of L-CPTI spanning these conserved C-terminal residues may be the region of the protein involved in binding the CoA moiety of palmitoyl-CoA and malonyl-CoA and/or the putative low affinity acyl-CoA/malonyl-CoA binding site [6].
• We presently analyzed at both the functional and structural levels five missense mutations identified in three CPT1A-deficient patients, namely A275T, A414V, Y498C, G709E, and G710E [1].
• In addition to coordinating these enzymes, CAR plays other roles in hepatic gene expression: CAR represses various genes including carnitine palmitoyltransferase 1a and phosphoenolpyruvate carboxykinase 1 in response to PB, and the receptor regulates the constitutive expression of genes such as squalene epoxidase [7].
• However, the up-regulation of CPT-I did not directly reflect the enzyme activity of CPT-I [8].

Anatomical context of Cpt1a

• The degradation of fatty acids occurs in mitochondria and is catalyzed by several carnitine acyl transferases, including two carnitine palmitoyl transferases, CPT-I and CPT-II [9].
• Expression of genes for carnitine palmitoyltransferase 1A and fatty acid oxidation was increased in epididymal but not subcutaneous fat [10].
• We determined two putative lipid messengers, 1,2-diacylglycerol (DAG) and ceramide, in JVS and carnitine palmitoyltransferase-I (CPT-I) inhibitor etomoxir-treated mice because these lipids function as co-messengers in the myocardium via modification of protein kinase C activity [11].

Associations of Cpt1a with chemical compounds

• Using gel shift, glutathione S-transferase pull-down and cell-based reporter assays, we then examined whether PXR could cross-talk with the insulin response forkhead factor FoxA2 to repress the transcription of the Cpt1a and Hmgcs2 genes, because FoxA2 activates these genes in fasting liver [2].
• Carnitine palmitoyltransferase-I (CPT-I) catalyzes the rate-controlling step of fatty acid oxidation [5].
• Substitution of Glu-603 with alanine or histidine resulted in complete loss of L-CPTI activity [6].
• Carnitine palmitoyltransferase I (CPTI) catalyzes the conversion of long chain fatty acyl-CoAs to acylcarnitines in the presence of l-carnitine [6].
• Substitution of Glu-603 with aspartate, a negatively charged amino acid with only one methyl group less than the glutamate residue in the wild type enzyme, resulted in partial loss in CPTI activity and a 15-fold decrease in malonyl-CoA sensitivity [6].

Other interactions of Cpt1a

• Cpt1a mapped to the centromeric region of Chr 19, 8.7 cM proximal to Pomc-ps1 [12].
• The genes for the two isoforms of CPTI-liver (L-CPTI) and muscle (M-CPTI) have been cloned and expressed, and the genes encode for enzymes with very different kinetic properties and sensitivity to malonyl-CoA inhibition [13].
• In HepG2 cells, CUDA increased the expression of the PPARalpha-responsive gene carnitine palmitoyltransferase 1A [14].

Analytical, diagnostic and therapeutic context of Cpt1a

• To determine the possible reversibility of the age change in CPT-I activity, we studied the effect of oral administration of propionyl-L-carnitine (PLC) [15].

References