Niacin in Pharmacological Doses Alters MicroRNA Expression in Skeletal Muscle of Obese Zucker Rats

Abstract

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.

Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans

“…Less is known about potential regulatory roles of other vitamins, including those that function as true enzyme cofactors in the metabolic network. However, gene expression profiling in mammalian cells has revealed transcript-level responses to vitamins B1 (thiamine) ( Fraser et al, 2012 ; Liu et al, 2004 ) ( Tanaka et al, 2007 ), B2 (riboflavin) ( Nakano et al, 2011 ), B3 (nicotinamide/niacin) ( Choi et al, 2011 ; Couturier et al, 2014 ; Giammona et al, 2006 ), B6 (pyridoxal 5′ phosphate, PLP) ( Toya et al, 2012 ; Zhang et al, 2014 ), B9 (folic acid) ( Barua et al, 2014 ; Champier et al, 2012 ; Lin et al, 2011 ), C (ascorbic acid) ( Canali et al, 2014 ; Jun et al, 2011 ; Takahashi et al, 2014 ), and E (tocopherol/tocotrienols) ( Landrier et al, 2010 ; Makpol et al, 2013 ; Mustacich et al, 2009 ). The mechanisms behind, and consequences of, these observed vitamin-induced gene expression changes have yet to be elucidated.…”

Niacin promotes revascularization and recovery of limb function in diet‐induced obese mice with peripheral ischemia

“…In fact, niacin has recently been shown to alter gene expression, including factors involved in Wnt signaling, in skeletal muscle of obese Zucker rats (Couturier et al. ).…”

Hepatic transcript profiling in early-lactation dairy cows fed rumen-protected niacin during the transition from late pregnancy to lactation

“…Interestingly, a single miRNA can regulate hundreds of protein-encoding target mRNAs, indicating the great regulatory potential of miRNAs (Bartel, 2004). We recently demonstrated in a study with rats that NA at a pharmacologic dosage alters the expression of miRNAs in skeletal muscle, and in silico target gene prediction indicated that more than 1,800 mRNAs are putative targets of NA-regulated miRNAs (Couturier et al, 2014). Moreover, we showed that many of the predicted target mRNAs from the most strongly downregulated miRNAs are involved in transcription regulator activity and regulation of transcription from RNA polymerase, indicating that processes dealing with gene transcription are activated by NA treatment because the mRNAs from downregulated miRNAs are less targeted and, thus, less degraded.…”

“…Moreover, we showed that many of the predicted target mRNAs from the most strongly downregulated miRNAs are involved in transcription regulator activity and regulation of transcription from RNA polymerase, indicating that processes dealing with gene transcription are activated by NA treatment because the mRNAs from downregulated miRNAs are less targeted and, thus, less degraded. Interestingly, the recent rat study also showed that several stressresponsive transcription factors including ATF3, ATF1, and one member of the E2F family, E2F7, are targets of the miRNAs downregulated by NA (Couturier et al, 2014). In the liver of cows fed rumen-protected NA, 831 mRNAs were predicted as targets of the 10 most strongly downregulated miRNAs.…”