Disease relevance of CPT1A

• A significant association between obesity phenotypes (BMI, weight, and waist girth) and CPT1B c.282-18C > T and p.E531K variants was observed (p < 0.05) No other association was found with variants in CPT1A and CPT1B [1].
• L-CPT1 deficiency (13 families reported) presents as recurrent attacks of fasting hypoketotic hypoglycemia [2].
• We conclude that hyperglycemia with hyperinsulinemia increases malonyl-CoA, inhibits functional CPT-1 activity, and shunts LCFA away from oxidation and toward storage in human muscle [3].
• We hypothesized that the transfer of long-chain fatty acids (LCFAs) into the mitochondria via carnitine palmitoyltransferase-1 (CPT-1) is inhibited by increased malonyl coenzyme A (malonyl-CoA) (a known potent inhibitor of CPT-1) in human muscle during hyperglycemia with hyperinsulinemia [3].
• In the present study we have identified and characterized the mutations underlying L-CPT I deficiency in six patients: five with classic symptoms of L-CPT I deficiency and one with symptoms that have not previously been associated with this disorder (muscle cramps and pain) [4].

Psychiatry related information on CPT1A

• Inhibition of CPT1A activity normalized the hypothalamic levels of LCFA-CoAs and markedly inhibited feeding behavior and hepatic glucose fluxes in overfed rats [5].

High impact information on CPT1A

• Fatty acid oxidation and ketogenesis are stimulated simultaneously with a paradoxical stimulation of fatty acid synthesis, which may be linked by virtue of a blunted response of mitochondrial carnitine palmitoyltransferase I (CPT-I) to malonyl coenzyme A (CoA) [6].
• To this end, we targeted the liver isoform of carnitine palmitoyltransferase-1 (encoded by the CPT1A gene) by infusing either a sequence-specific ribozyme against CPT1A or an isoform-selective inhibitor of CPT1A activity in the third cerebral ventricle or in the mediobasal hypothalamus (MBH) [5].
• In addition, a missense SNP in the carnitine palmitoyltransferase 1A (CPT1A) gene was associated with a decreased risk of advanced fibrosis in both the UCSF and the VCU cohorts (OR, 0.3 and 0.6, respectively) [7].
• RESULTS: Hepatic concentrations of PPARalpha and CPT1A expressed by hepatocytes were impaired profoundly in the livers of untreated patients with HCV infection compared with controls [8].
• PPARalpha activity was assessed by quantification of the key gene target carnitine palmitoyl acyl-CoA transferase 1 (CPT1A) messenger RNA (mRNA).The influence of HCV core protein on PPARalpha mRNA expression was analyzed in vitro by real-time PCR in HCV core-expressing HepG2 cells activated with the PPARalpha ligand fenofibric acid [8].

Chemical compound and disease context of CPT1A

• BACKGROUND: Genistein increases CPT1A, a rate-limiting enzyme in the beta-oxidation pathway, enzyme activity by increasing CPT1A transcription in HepG2 cells and, consequently, suppresses high fat induced obesity in C57BL/6J mice [9].
• The objective was to verify whether variants in the gene encoding the carnitine palmitoyltransferase I (CPT1), a key enzyme in beta-oxidation of fatty acids, are associated with obesity phenotypes, alone or in interaction with fat intake [1].

Biological context of CPT1A

• We have shown that this sequence is fundamental for fatty acids or PGC1-induced transcriptional activation of the CPT1A gene [10].
• Using Web-based software (VISTA) combining transcription factor binding site database searches with comparative sequence analyses, we have localized a conserved functional PPAR responsive element downstream of the transcriptional start site of the human CPT1A gene [10].
• Northern blotting revealed differences in tissue distribution for both CPT1A and CPT1B transcripts compared with other species [11].
• Fine chromosome mapping of the genes for human liver and muscle carnitine palmitoyltransferase I (CPT1A and CPT1B) [12].
• Nine variants within CPT1B and one variant within CPT1A were selected for further analyses based on the minor allele frequency (>10%) or on potential functional impact [1].

Anatomical context of CPT1A

• Studies in fibroblasts from one patient as well as heterologous expression of the mutagenized CPT1A in yeast show that the G710E mutation alters neither mitochondrial targeting nor stability of the CPT1A protein [13].
• CPT-I and CPT-II are crucial for the beta-oxidation of long-chain fatty acids in the mitochondria by enabling their transport across the mitochondrial membrane [14].
• An intronic peroxisome proliferator-activated receptor-binding sequence mediates fatty acid induction of the human carnitine palmitoyltransferase 1A [10].
• Northern blot analysis of other rat tissues established L-CPT I as the dominant isoform not only in liver but also in kidney, lung, ovary, spleen, brain, intestine and pancreatic islets [15].
• Transfection of the mutant L-CPT I cDNAs in COS cells resulted in L-CPT I mRNA levels that were comparable to those expressed from the wild-type construct [4].

Associations of CPT1A with chemical compounds

• While a major role for PPARalpha in the liver is to produce ketone bodies as fuel through beta-oxidation for peripheral tissues during fast, its participation in the control of CPT1A, the rate-limiting step of the pathway, remains controversial [10].
• Organization of the human liver carnitine palmitoyltransferase 1 gene ( CPT1A) and identification of novel mutations in hypoketotic hypoglycaemia [16].
• In contrast, HepG2 cells seemed to be resistant to PPARalpha activation by 13-HPODE because no remarkable induction of the PPARalpha target genes ACO, CPT1A, mitochondrial HMG-CoA synthase and delta9-desaturase was observed [17].
• We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease [18].
• Natural mutation of Pro(479), which is also located in the malonyl-CoA predicted site, to Leu in a patient with human L-CPT I hereditary deficiency, modified malonyl-CoA sensitivity [19].

Regulatory relationships of CPT1A

• Both glucagon and 3,3',5-tri-iodothyronine (T(3)) enhanced the transcription of the gene encoding L-CPT I, whereas insulin had the opposite effect [20].

Other interactions of CPT1A

• Data from the human genome sequencing efforts now reveal drafts of the genomic structure of CPT1A and CRAT, the latter not being known from any other mammal [21].
• Carnitine treated patients showed a rise in plasma carnitine which led to an increase of relative mRNA levels from CPT1A (liver isoform of carnitine palmitoyltransferase) and OCTN2 (carnitine transporter) [22].
• Fenofibrate increased PPARalpha (62%, P <.05) and LOX-1 (180%, P <.05) mRNA levels; and troglitazone upregulated CPT-I expression (75%, P <.05) [23].
• In this report, we showed that genistein, one of the major isoflavones, increased expression of genes involved in lipid catabolism such as carnitine palmitoyltransferase 1, liver form (CPT1L) in HepG2 cells, when assayed by real-time reverse-transcriptase polymerase chain reactions as well as Western blotting analysis [24].
• The increase in mRNA-level of CPT1L after genistein treatment was not changed in the presence of ICI182780, a potent inhibitor of estrogen receptor, suggesting that this effect of genistein was estrogen receptor-independent [24].

Analytical, diagnostic and therapeutic context of CPT1A

• Similar results were obtained with the CPT1A p.A275T variant as BMI and waist girth were higher in A275/A275 on a high fat compared to A275/A275 subjects on a low-fat diet [1].
• Because CPT1A is involved in lipid metabolism and CPT1A deficiency in human is associated with the hypoketotic hypoglycemia disorder, the reduced CPT1A expression in hESC-NPCs raises a potential concern for the suitability of these cells in cell transplantation [25].
• Consistently, DCM patients had a significantly higher cardiac CPT-1 mRNA expression (147+/-51% vs. control, p<0.05) compared to the control group [26].
• In vivo inhibition of angiogenesis was determined by the disc angiogenesis system (DAS), where surgical sponge discs were placed subcutaneously in the rat dorsum and the ability of systemic treatment with liposomal CPT (LCPT), TPT, TNP-470 or cisplatin to inhibit vascular growth into the discs was evaluated [27].
• Molecular cloning techniques have demonstrated that two CPT-I isoforms exist as genes encoding the 'muscle' and 'liver' enzymes [28].

References