Abstract
BackgroundMicroRNAs (miRNAs) are small regulatory molecules which post-transcriptionally regulate mRNA stability and translation. Several microRNAs have received attention due to their role as key metabolic regulators. In spite of the high evolutionary conservation of several miRNAs, the role of miRNAs in lower taxa of vertebrates has not been studied with regard to metabolism. The liver-specific and highly abundant miRNA-122 is one of the most widely studied miRNA in mammals, where it has been implicated in the control of hepatic lipid metabolism. Following our identification of acute postprandial, nutritional and endocrine regulation of hepatic miRNA-122 isomiRNA expression in rainbow trout, we used complementary in silico and in vivo approaches to study the role of miRNA-122 in rainbow trout metabolism. We hypothesized that the role of miRNA-122 in regulating lipid metabolism in rainbow trout is conserved to that in mammals and that modulation of miRNA-122 function would result in altered lipid homeostasis and secondarily altered glucose homeostasis, since lipogenesis has been suggested to act as glucose sink in trout.ResultsOur results show that miRNA-122 was functionally inhibited in vivo in the liver. Postprandial glucose concentrations increased significantly in rainbow trout injected with a miRNA-122 inhibitor, and this effect correlated with decreases in hepatic FAS protein abundance, indicative of altered lipogenic potential. Additionally, miRNA-122 inhibition resulted in a 20% decrease in plasma cholesterol concentration, an effect associated with increased expression of genes involved in cholesterol degradation and excretion.ConclusionsOverall evidence suggests that miRNA-122 may have evolved in early vertebrates to support liver-specific metabolic functions. Nevertheless, our data also indicate that metabolic consequences of miRNA-122 inhibition may differ quantitatively between vertebrate species and that distinct direct molecular targets of miRNA-122 may mediate metabolic effects between vertebrate species, indicating that miRNA-122 - mRNA target relationships may have undergone species-specific evolutionary changes.
Highlights
MicroRNAs are small regulatory molecules which post-transcriptionally regulate mRNA stability and translation
We have previously shown that a specific isoform of miRNA-122, omy-miRNA-122b, is postprandially regulated in rainbow trout [14], and that this regulation depends on macronutrient composition and the endocrine factor insulin [15], a key metabolic hormone
Pharmacological modulation of rainbow trout by the antidiabetic drug metformin resulted in improved postprandial glucose clearance, but in contrast to mammals, this effect was not correlated with a repression of hepatic gluconeogenic gene expression, but rather with an induction of hepatic lipogenic gene expression [20], providing further evidence for an involvement of hepatic de novo lipogenesis in glucose clearance in rainbow trout
Summary
MicroRNAs (miRNAs) are small regulatory molecules which post-transcriptionally regulate mRNA stability and translation. We have previously shown that a specific isoform of miRNA-122, omy-miRNA-122b, is postprandially regulated in rainbow trout [14], and that this regulation depends on macronutrient composition and the endocrine factor insulin [15], a key metabolic hormone These findings led us to investigate the function of miRNA-122 in rainbow trout, which, in spite of its high degree of evolutionary conservation [16], has not been characterized functionally in lower vertebrates. In order to investigate a possible role for miRNA-122 in coordinating postprandial glucose homeostasis through the modulation of lipid metabolism, we used an in vivo approach by blocking the activity of miRNA-122 using a short LNA-miRNA-122 inhibitor (LNA-122i) [25] This approach was complemented by in silico approaches to predict potential direct mRNA targets of miR-122 in rainbow trout, as well as to predict potentially regulated pathways
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