Abstract
BackgroundActivation of peroxisome proliferator-activated receptor (PPAR)α and PPARδ causes an elevation of tissue carnitine concentrations through induction of genes involved in carnitine uptake [novel organic cation transporter 2, (OCTN2)], and carnitine biosynthesis [γ-butyrobetaine dioxygenase (BBD), 4-N-trimethyl-aminobutyraldehyde dehydrogenase (TMABA-DH)]. Recent studies showed that administration of the plasma lipid-lowering drug niacin causes activation of PPARα and/or PPARδ in tissues of obese Zucker rats, which have a compromised carnitine status and an impaired fatty acid oxidation capacity. Thus, we hypothesized that niacin administration to obese Zucker rats is also able to improve the diminished carnitine status of obese Zucker rats through PPAR-mediated stimulation of genes involved in carnitine uptake and biosynthesis.MethodsTo test this hypothesis, we used plasma, muscle and liver samples from a recent experiment with obese Zucker rats, which were fed either a niacin-adequate diet (30 mg niacin/kg diet) or a diet with a pharmacological niacin dose (780 mg niacin/kg diet), and determined concentrations of carnitine in tissues and mRNA and protein levels of genes critical for carnitine homeostasis (OCTN2, BBD, TMABA-DH). Statistical data analysis of all data was done by one-way ANOVA, and Fisher’s multiple range test.ResultsRats of the obese niacin group had higher concentrations of total carnitine in plasma, skeletal muscle and liver, higher mRNA and protein levels of OCTN2, BBD, and TMABA-DH in the liver and higher mRNA and protein levels of OCTN2 in skeletal muscle than those of the obese control group (P < 0.05), whereas rats of the obese control group had lower concentrations of total carnitine in plasma and skeletal muscle than lean rats (P < 0.05).ConclusionThe results show for the first time that niacin administration stimulates the expression of genes involved in carnitine uptake and biosynthesis and improves the diminished carnitine status of obese Zucker rats. We assume that the induction of genes involved in carnitine uptake and biosynthesis by niacin administration is mediated by PPAR-activation.
Highlights
Activation of peroxisome proliferator-activated receptor (PPAR)α and PPARδ causes an elevation of tissue carnitine concentrations through induction of genes involved in carnitine uptake [novel organic cation transporter 2, (OCTN2)], and carnitine biosynthesis [γ-butyrobetaine dioxygenase (BBD), 4-N-trimethyl-aminobutyraldehyde dehydrogenase (TMABA-DH)]
In addition to its function in fatty acid catabolism, it has been recently established that PPARα and PPARδ are transcriptional regulators of genes involved in carnitine uptake, like novel organic cation transporter 2 (OCTN2, encoded by SLC22A5) [12,14], and/or carnitine biosynthesis, such as γ-butyrobetaine dioxygenase (BBD, encoded by BBOX1) and 4-N-trimethyl-aminobutyraldehyde dehydrogenase (TMABA-DH, encoded by ALDH9) [15,16]
In the present study, we tested the hypothesis that niacin administration to obese Zucker rats is able to improve the carnitine status of obese Zucker rats through PPARstimulated expression of genes involved in carnitine uptake and biosynthesis
Summary
Activation of peroxisome proliferator-activated receptor (PPAR)α and PPARδ causes an elevation of tissue carnitine concentrations through induction of genes involved in carnitine uptake [novel organic cation transporter 2, (OCTN2)], and carnitine biosynthesis [γ-butyrobetaine dioxygenase (BBD), 4-N-trimethyl-aminobutyraldehyde dehydrogenase (TMABA-DH)]. In addition to its function in fatty acid catabolism, it has been recently established that PPARα and PPARδ are transcriptional regulators of genes involved in carnitine uptake, like novel organic cation transporter 2 (OCTN2, encoded by SLC22A5) [12,14], and/or carnitine biosynthesis, such as γ-butyrobetaine dioxygenase (BBD, encoded by BBOX1) and 4-N-trimethyl-aminobutyraldehyde dehydrogenase (TMABA-DH, encoded by ALDH9) [15,16] This explains why physiological or pharmacological PPARα and PPARδ activation causes an elevation of carnitine concentrations in tissues because both, carnitine uptake and biosynthesis is stimulated [14,17,18]. Transcriptional regulation of genes involved in carnitine homeostasis by PPARα and PPARδ is in line with their fundamental role for fatty acid catabolism because oxidation of fatty acids requires their import into the mitochondrial matrix, which is dependent on carnitine
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