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Pharmacological doses of niacin stimulate the expression of genes involved in carnitine uptake and biosynthesis and improve the carnitine status of obese Zucker rats.

ABSTRACT: BACKGROUND: Activation of peroxisome proliferator-activated receptor (PPAR)? and PPAR? causes an elevation of tissue carnitine concentrations through induction of genes involved in carnitine uptake [novel organic cation transporter 2, (OCTN2)], and carnitine biosynthesis [?-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 PPAR? and/or PPAR? 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. METHODS: To 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. RESULTS: Rats 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?

SUBMITTER: Couturier A

PROVIDER: S-EPMC4094635 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Project description:Administration of pharmacological niacin doses was recently reported to have pronounced effects on skeletal muscle gene expression and phenotype in obese Zucker rats, with the molecular mechanisms underlying the alteration of gene expression being completely unknown. Since miRNAs have been shown to play a critical role for gene expression through inducing miRNA-mRNA interactions which results in the degradation of specific mRNAs or the repression of protein translation, we herein aimed to investigate the influence of niacin at pharmacological doses on the miRNA expression profile in skeletal muscle of obese Zucker rats fed either a control diet with 30 mg supplemented niacin/kg diet or a high-niacin diet with 780 mg supplemented niacin/kg diet for 4 wk. miRNA microarray analysis revealed that 42 out of a total of 259 miRNAs were differentially expressed (adjusted P-value <0.05), 20 being down-regulated and 22 being up-regulated, between the niacin group and the control group. Using a biostatistics approach, we could demonstrate that the most strongly up-regulated (log2 ratio ≥0.5) and down-regulated (log2 ratio ≤-0.5) miRNAs target approximately 1,800 mRNAs. Gene-term enrichment analysis showed that many of the predicted target mRNAs from the most strongly regulated miRNAs were involved in molecular processes dealing with gene transcription such as DNA binding, transcription regulator activity, transcription factor binding and in important regulatory pathways such as Wnt signaling and MAPK signaling. In conclusion, the present study shows for the first time that pharmacological niacin doses alter the expression of miRNAs in skeletal muscle of obese Zucker rats and that the niacin-regulated miRNAs target a large set of genes and pathways which are involved in gene regulatory activity indicating that at least some of the recently reported effects of niacin on skeletal muscle gene expression and phenotype in obese Zucker rats are mediated through miRNA-mRNA interactions.

Project description:BackgroundIn the past, numerous studies revealed that supplementation with carnitine has multiple effects on performance characteristics and gene expression in livestock and model animals. The molecular mechanisms underlying these observations are still largely unknown. Increasing evidence suggests that microRNAs (miRNAs), a class of small non-coding RNA molecules, play an important role in post-transcriptional regulation of gene expression and thereby influencing several physiological and pathological processes. Based on these findings, the aim of the present study was to investigate the influence of carnitine supplementation on the miRNA expression profile in skeletal muscle of obese Zucker rats using miRNA microarray analysis.ResultsObese Zucker rats supplemented with carnitine had higher concentrations of total carnitine in plasma and muscle than obese control rats (P < 0.05). miRNA expression profiling in skeletal muscle revealed a subset of 152 miRNAs out of the total number of miRNAs analysed (259) were identified to be differentially regulated (adjusted P-value < 0.05) by carnitine supplementation. Compared to the obese control group, 111 miRNAs were up-regulated and 41 down-regulated by carnitine supplementation (adjusted P-value < 0.05). 14 of these miRNAs showed a log2 ratio ≥ 0.5 and 7 miRNAs showed a log2 ratio ≤ -0.5 (adjusted P-value < 0.05). After confirmation by qRT-PCR, 11 miRNAs were found to be up-regulated and 6 miRNAs were down-regulated by carnitine supplementation (P < 0.05). Furthermore, a total of 1,446 target genes within the validated miRNAs were revealed using combined three bioinformatic algorithms. Analysis of Gene Ontology (GO) categories and KEGG pathways of the predicted targets revealed that carnitine supplementation regulates miRNAs that target a large set of genes involved in protein-localization and -transport, regulation of transcription and RNA metabolic processes, as well as genes involved in several signal transduction pathways, like ubiquitin-mediated proteolysis and longterm depression, are targeted by the miRNAs regulated by carnitine supplementation.ConclusionThe present study shows for the first time that supplementation of carnitine affects a large set of miRNAs in skeletal muscle of obese Zucker rats suggesting a novel mechanism through which carnitine exerts its multiple effects on gene expression, which were observed during the past.

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Pharmacological doses of niacin stimulate the expression of genes involved in carnitine uptake and biosynthesis and improve the carnitine status of obese Zucker rats.

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