ABSTRACT
BACKGROUND/AIMS: Juvenile visceral steatosis (jvs-/-) mice lack the activity of the carnitine transporter OCTN2 and are dependent on carnitine substitution. The effects of carnitine deprivation on carnitine homeostasis and energy metabolism are not known in jvs-/- mice. METHODS: jvs-/- mice were studied 3, 6 and 10 days after carnitine deprivation, and compared to jvs-/- mice substituted with carnitine, wild-type (jvs+/+) and jvs+/- mice. Carnitine concentrations were assessed radioenzymatically. RESULTS: Compared to wild-type mice, carnitine-treated jvs-/- mice had decreased plasma beta-hydroxybutyrate levels and showed hepatic fat accumulation. The carnitine levels in plasma, liver and skeletal muscle were decreased by 58, 16 and 17%, respectively. After ten days of carnitine deprivation, the plasma carnitine concentration had fallen by 87% (to 2.3 mumol/l) and the tissue carnitine levels by approximately 50% compared to carnitine-treated jvs-/- mice. Carnitine deprivation was associated with a further drop in plasma beta-hydroxybutyrate and increased hepatic fat. Skeletal muscle glycogen stores decreased and lactate levels increased with carnitine deprivation, whereas tissue ATP levels were maintained. CONCLUSIONS: In jvs-/- mice, tissue carnitine stores are more resistant than carnitine plasma concentrations to carnitine deprivation. Metabolic changes (liver steatosis and loss of muscle glycogen stores) appear also early after carnitine deprivation.
Subject(s)
3-Hydroxybutyric Acid/blood , Carnitine/deficiency , Energy Metabolism , Lipid Metabolism, Inborn Errors/metabolism , Organic Cation Transport Proteins/deficiency , Adenosine Triphosphate/analysis , Animals , Body Weight , Carnitine/administration & dosage , Carnitine/metabolism , Carnitine/therapeutic use , Fatty Liver/etiology , Fatty Liver/genetics , Fatty Liver/metabolism , Fatty Liver/pathology , Genotype , Glycogen/analysis , Homeostasis , Lactates/analysis , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/pathology , Liver/chemistry , Liver/pathology , Mice , Mice, Knockout , Muscle, Skeletal/chemistry , Muscle, Skeletal/pathology , Organ Size , Organic Cation Transport Proteins/genetics , Solute Carrier Family 22 Member 5ABSTRACT
The aim of this study was to investigate whether a decrease in carnitine body stores is a risk factor for valproic acid (VPA)-associated hepatotoxicity and to explore the effects of VPA on carnitine homeostasis in mice with decreased carnitine body stores. Therefore, heterozygous juvenile visceral steatosis (jvs)(+/-) mice, an animal model with decreased carnitine stores caused by impaired renal reabsorption of carnitine, and the corresponding wild-type mice were treated with subtoxic oral doses of VPA (0.1 g/g b.wt./day) for 2 weeks. In jvs(+/-) mice, but not in wild-type mice, treatment with VPA was associated with the increased plasma activity of aspartate aminotransferase and alkaline phosphatase. Furthermore, jvs(+/-) mice revealed reduced palmitate metabolism assessed in vivo and microvesicular steatosis of the liver. The creatine kinase activity was not affected by treatment with VPA. In liver mitochondria isolated from mice that were treated with VPA, oxidative metabolism of l-glutamate, succinate, and palmitate, as well as beta-oxidation of palmitate, were decreased compared to vehicle-treated wild-type mice or jvs(+/-) mice. In comparison to vehicle-treated wild-type mice, vehicle-treated jvs(+/-) mice had decreased carnitine plasma and tissue levels. Treatment with VPA was associated with an additional decrease in carnitine plasma (wild-type mice and jvs(+/-) mice) and tissue levels (jvs(+/-) mice) and a shift of the carnitine pools toward short-chain acylcarnitines. We conclude that jvs(+/-) mice reveal a more accentuated hepatic toxicity by VPA than the corresponding wild-type mice. Therefore, decreased carnitine body stores can be regarded as a risk factor for hepatotoxicity associated with VPA.
