Disease relevance of Carnitine

• Short-chain acyl-CoA dehydrogenase deficiency associated with a lipid-storage myopathy and secondary carnitine deficiency [1].
• Serum carnitine in Reye's syndrome [2].
• A disorder of muscle lipid metabolism and myoglobinuria. Absence of carnitine palmityl transferase [3].
• Brief report: renal tubular acidosis in carnitine palmitoyltransferase type 1 deficiency [4].
• Systemic carnitine deficiency presenting as familial endocardial fibroelastosis: a treatable cardiomyopathy [5].

Psychiatry related information on Carnitine

• We therefore assessed carnitine acetyl-transferase activity in selected brain regions and in isolated cerebral microvessels obtained at autopsy from patients with Alzheimer's disease and from age-matched control subjects [6].
• In patients with primary carnitine deficiencies, which may be life-threatening, and some secondary deficiencies such as organic acidurias, the exogenously administered compound is clearly beneficial: by abolishing hypotonia, motor skills are improved, as are muscle weakness and wasting [7].
• Acetyl-L-carnitine (ALCAR) is the acetyl ester of carnitine that has been reported to be beneficial in depressive disorders and Alzheimer's disease [8].
• The 10-wk, randomized, double-blind intervention consisted of a hypoenergetic diet, high in protein (30% energy) and low in carbohydrate (40% energy), increased physical activity (number of steps taken per day), and intake of a supplement (carnitine or placebo) [9].
• These results demonstrate that the BoNTx-lesioned rat can be used as a model for dementia and that cognitive deficits can be alleviated in part by BDNF gene transfer or carnitine administration [10].

High impact information on Carnitine

• The role of the various lipid-binding proteins in transmembrane and cytosolic transport of lipids is considered as well as regulation of lipid entry into the mitochondria, focusing on the putative role of AMP-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC), and carnitine during exercise [11].
• Although a carnitine translocase that allows carnitine and acylcarnitine to penetrate the inner mitochondrial membrane has been deduced from functional studies (see Fig. 5), this translocase has not been isolated as a protein separate from the acyltransferases [12].
• Carnitine acetyltransferase and carnitine octanoyltransferase are also found in the peroxisomes [12].
• Our observation that OCTN2 has the ability to transport carnitine in a sodium-dependent manner prompted us to search for mutations in the gene encoding OCTN2, SLC22A5 [13].
• Renal function was assessed by measurements of proteinuria, urinary volume, and fractional excretions of potassium, phosphate, carnitine, and amino acids [14].

Chemical compound and disease context of Carnitine

• Partial muscle carnitine palmitoyltransferase-A deficiency. Rhabdomyolysis associated with transiently decreased muscle carnitine content after ibuprofen therapy [15].
• Because oral L-carnitine corrects plasma carnitine deficiency, lowers plasma free fatty acid concentrations, and reverses muscle lipid accumulation in some patients, its use as therapy in renal Fanconi syndrome should be considered [16].
• Two cystinotic patients fasted for 24 h and one idiopathic Fanconi syndrome patient fasted for 5 h showed normal increases in plasma beta-hydroxybutyrate and acetoacetate, which suggested that hepatic fatty acid oxidation was intact despite very low plasma free carnitine levels [17].
• C75 is a small-molecule inhibitor of fatty acid synthase (FAS) and a stimulator of carnitine palmitoyl 1 activity, which causes profound weight loss in mice [18].
• The discovery of this previously unappreciated relationship between OCTN2, carnitine, and hepatic triglyceride production is of particular importance because of the clinical consequence of hypertriglyceridemia and the paucity of genes known to modulate triglyceride secretion [19].

Biological context of Carnitine

• Pivalate-generating prodrugs and carnitine homeostasis in man [20].
• The results are consistent with the possibility that the activity of carnitine acyltransferase, and thus ketogenic capacity, is subject to bihormonal control through the relative blood concentrations of insulin and glucagon, as also appears to be the case with hepatic carbohydrate metabolism [21].
• A total deficiency of the carnitine-acyl-carnitine translocase was found in fibroblasts using the carnitine acetylation assay (1986. Biochem. J. 236:143-148) [22].
• Carnitine transport in human intestinal biopsy specimens. Demonstration of an active transport system [23].
• We have studied small intestinal absorption of carnitine in vivo using a combination of segmental perfusion techniques and bolus intraluminal injection [24].

Anatomical context of Carnitine

• The carnitine-dependent transport of activated fatty acids across the mitochondrial membrane is a regulated process [12].
• Carnitine concentrations in the skeletal muscle and liver were moderately reduced, but carnitine deficiency was considered a secondary biochemical abnormality [25].
• Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle, and fibroblasts [26].
• Membrane-physiological studies have suggested a defect of the carnitine transport system in the plasma membrane in SCD patients and in the mouse model, juvenile visceral steatosis [13].
• In isolated liver mitochondria, state 3 oxidation rates were unchanged or decreased, and activities of the mitochondrial enzymes, citrate synthetase, succinate dehydrogenase, carnitine palmitoyltransferase, and glutamate dehydrogenase (expressed per milligram mitochondrial protein) were unaffected by HCCL treatment [27].

Associations of Carnitine with other chemical compounds

• We report the crystal structures of murine carnitine acetyltransferase (CRAT), alone and in complex with its substrate carnitine or CoA [28].
• Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle [29].
• Measurements in fibroblasts confirmed deficient oxidation of palmitate and showed normal activities of the carnitine palmitoyltransferases I and II and of the three acyl-CoA dehydrogenases [22].
• Thus, the current studies illustrate the close interaction between the CoA and carnitine pools in the exercising human skeletal muscle, and they underscore the important role of carnitine in maintaining the muscular CoASH content during exhaustive exercise [30].
• Also, the preference for choline over carnitine as an acetyl acceptor is seen to result from both electrostatic and steric blocks to carnitine binding at the active site [31].

Gene context of Carnitine

• The carnitine/organic cation transporter (OCTN) on 5q31 (IBD5) is associated with Crohn's disease (CD) and DLG5 (10q23), a member of membrane-associated guanylate kinase (MAGUK) family, with IBD [32].
• Molecular characterization of carnitine-dependent transport of acetyl-CoA from peroxisomes to mitochondria in Saccharomyces cerevisiae and identification of a plasma membrane carnitine transporter, Agp2p [33].
• By contrast, the carnitine transporter OCTN2 from rat did not transport ET at all [34].
• Because ET is transported >100 times more efficiently than tetraethylammonium and carnitine, we propose the functional name ETT (ET transporter) instead of OCTN1 [34].
• These analyses demonstrated that ACC1 is a cytosolic protein and that ACC2 was associated with the mitochondria, a finding that was confirmed further by the immunocolocalization of a known human mitochondria-specific protein and the carnitine palmitoyltransferase 1 [35].

Analytical, diagnostic and therapeutic context of Carnitine

• Animal models and long-term treatment of patients with pivalate prodrugs have resulted in toxicity consistent with carnitine depletion [20].
• Carnitine status of continuous ambulatory peritoneal dialysis patients [36].
• The mean total and free plasma carnitine concentrations and the mean total hepatic carnitine concentration were reduced before supplementation and rose to normal values after treatment (27.4 +/- 2.3 to 35.5 +/- 3.1 nmol/ml, 19.4 +/- 2.8 to 25.7 +/- 2.5 nmol/ml, and 3.5 +/- 0.65 to 6.5 +/- 1.2 nmol/mg of noncollagen protein, respectively) [37].
• Intravenous infusion of carnitine produced the same effects [38].
• All patients had abnormalities in standard liver function tests and low total and free plasma carnitine values [37].

References