Disease relevance of Cpt1a

• The effects of the inhibition of carnitine palmitoyltransferase I (CPT-I), a key enzyme for transport of long chain fatty acids (LCFA) into the mitochondria, on ischemia/reperfusion (I/R) injury are unknown [1].

High impact information on Cpt1a

• In addition, PGC-1 alpha will stimulate the expression of CPT-I alpha in primary rat hepatocytes [2].
• Carnitine palmitoyltransferase I (CPT-I) catalyzes the rate-controlling step in the pathway of mitochondrial fatty acid oxidation [2].
• Using mass spectrometry, only one region of phosphorylation was detected in CPT-I isolated from CKII-treated mitochondria [3].
• Thyroid hormone will stimulate the expression of the liver isoform of CPT-I (CPT-I alpha) [2].
• Incubation of dephosphorylated outer membranes with protein kinases and [gamma-32P]ATP resulted in radiolabeling of CPT-I only by CKII [3].

Biological context of Cpt1a

• This induction of CPT-I alpha gene expression requires the thyroid hormone response element in the promoter and sequences within the first intron [2].
• These observations identify a new mechanism for regulation of hepatic CPT-I by phosphorylation [3].
• These data indicate that the catalytic subunit of CPTo/CPT-I is the same as CPTi/CPT-II [4].
• The presence of a malonyl-CoA/long chain acyl-CoA binding site on CPT-I, distinct from the inhibitory site, has previously been proposed [5].
• With these control measurements, the inhibition kinetics of CPT-I in the cardiac cells in situ maintains a partial competitive pattern which is more pronounced with decanoyl-CoA than with palmitoyl-CoA as substrate [5].

Anatomical context of Cpt1a

• The data used to support the idea that malonyl-coenzyme A (CoA)-sensitive carnitine palmitoyltransferase (CPT-I) is localized on the outer mitochondrial membrane are based on harsh techniques that disrupt mitochondrial physiology [6].
• In rat liver mitochondria, 4-THA inhibited carnitine palmitoyltransferase I (CPT-I) competitively with respect to the substrate palmitoyl-CoA, increasing the apparent Km from 19 microM to 86 microM [7].
• Following incubation in serum-free medium, there is a four-fold increase in the I50 of CPT-I for malonyl-CoA (3.8 microM) compared to cells cultured in serum-free medium to which insulin has been added (I50 = 0.8 microM) [8].
• Since carnitine-dependent fatty acid oxidation is modulated by insulin in a variety of tissues, the effects of 1.7 microM insulin on the mitochondrial enzyme(s), carnitine palmitoyltransferase (malonyl-CoA-sensitive CPT-I and the matrix-facing CPT-II), were studied in neonatal rat cardiac myocytes cultured in the absence of serum [8].
• There is no evidence in the cells for contamination of CPT-I activities by extramitochondrial sources, in particular, the sarcoplasmic reticulum (SR) [5].

Associations of Cpt1a with chemical compounds

• Furthermore, incubation of dephosphorylated outer membranes with CKII and unlabeled ATP led to increased catalytic activity and rendered malonyl-CoA inhibition of CPT-I from competitive to uncompetitive [3].
• The CoA ester of the monocarboxylic 3-thia fatty acid, tetradecylthioacetic acid, which accumulates in the liver after administration, inhibited the CPT-I activity in vitro, but not that of CPT-II [9].
• In Fao cells, 13-HPODE increased the mRNA concentration of the PPARalpha target genes acyl-CoA oxidase (ACO), cytochrome P450 4A1 and carnitine-palmitoyltransferase 1A (CPT1A) [10].
• Clofibric acid-induced suppression of glucose-simulated insulin secretion was prevented by the CPT-I inhibitor etomoxir [11].
• These results suggest that phospholipids are responsible for the increased inhibition of CPT by malonyl-CoA with added cholate extracts and that changes in membrane composition may be involved in the physiological regulation of CPT-I [12].

Physical interactions of Cpt1a

• It has been reported that sodium cholate can separate the catalytic component of carnitine palmitoyltransferase-I (CPT-I) from a putative malonyl-CoA-binding regulatory protein capable of conferring sensitivity to malonyl-CoA on CPT-II [12].

Regulatory relationships of Cpt1a

• The tetradecanamidomethyl analogue of (2R,6S)-1 activated CPT-I but inhibited CPT-II [13].
• This differential regulation of MCD expression and activity in the mitochondria by AMPK may potentially regulate malonyl-CoA levels at sites nearby CPT-I on the mitochondria [14].

Other interactions of Cpt1a

• Peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) enhances the thyroid hormone induction of carnitine palmitoyltransferase I (CPT-I alpha) [2].
• Moreover, an IGF-I analogue that inhibits the autophosphorylation of the IGF-I receptor blunts the insulin-mediated increase in CPT-I and -II activities by > 70% [15].
• The outer membrane fraction, which consisted of membrane "ghosts," contained most (50-60%) of marker enzyme activity, monoamine oxidase-B and porin proteins, but only about 27-29% CPT-I activity [6].
• Because CPT-I and long-chain acyl-CoA synthetase appear to be associated with both inner and outer membranes, we postulate that these enzymes reside in contact sites, which represent a melding of both limiting membranes [6].
• The mitochondrial carnitine palmitoyltransferase (CPT) system is composed of two proteins, CPT-I and -II, which, together with carnitine acylcarnitine translocase, are involved in the transport of fatty acids into the mitochondrial matrix for beta-oxidation [15].

Analytical, diagnostic and therapeutic context of Cpt1a

• Moreover, protein immunoblotting analysis showed that CPT-I, as well as the inner CPT-II, was localized in the mitoplast fraction [6].
• Our data also show that IP affords myocardial protection in CPT-I inhibited hearts to a degree similar to untreated animals, suggesting that a long-term treatment with the metabolic anti-ischemic agent Etomoxir does not impede the possibility to afford cardioprotection by ischemic preconditioning [1].

References