Energizing miRNA research: a review of the role of miRNAs in lipid metabolism, with a prediction that miR-103/107 regulates human metabolic pathways

Abstract

MicroRNAs (miRNAs) are powerful regulators of gene expression. Although first discovered in worm larvae, miRNAs play fundamental biological roles-including in humans-well beyond development. MiRNAs participate in the regulation of metabolism (including lipid metabolism) for all animal species studied. A review of the fascinating and fast-growing literature on miRNA regulation of metabolism can be parsed into three main categories: (1) adipocyte biochemistry and cell fate determination; (2) regulation of metabolic biochemistry in invertebrates; and (3) regulation of metabolic biochemistry in mammals. Most research into the 'function' of a given miRNA in metabolic pathways has concentrated on a given miRNA acting upon a particular 'target' mRNA. Whereas in some biological contexts the effects of a given miRNA:mRNA pair may predominate, this might not be the case generally. In order to provide an example of how a single miRNA could regulate multiple 'target' mRNAs or even entire human metabolic pathways, we include a discussion of metabolic pathways that are predicted to be regulated by the miRNA paralogs, miR-103 and miR-107. These miRNAs, which exist in vertebrate genomes within introns of the pantothenate kinase (PANK) genes, are predicted by bioinformatics to affect multiple mRNA targets in pathways that involve cellular Acetyl-CoA and lipid levels. Significantly, PANK enzymes also affect these pathways, so the miRNA and 'host' gene may act synergistically. These predictions require experimental verification. In conclusion, a review of the literature on miRNA regulation of metabolism leads us believe that the future will provide researchers with many additional energizing revelations.

Figure 1

MiRNAs function by recognizing a “target mRNA” and impairing the formation of a polypeptide from that mRNA. MiRNAs (purple) guide the Argonaute proteins (red) to a “target” mRNA (green). After miRNAs hybridize to a sequence on the 3′UTR (untranslated region) of the mRNA, the Argonaute protein helps to mediate translational inhibition and/or mRNA sequestration and degradation.

Figure 2

A. MiR-103 and miR-107 are paralogs, which differ only at a single nucleotide near the 3′ end of the miRNAs. B. For all known vertebrate species, each miR-103/107 paralog exists within an intron in a gene which also encodes the pantothenate kinase enzyme, PANK. PANK genes are shown with exons as rectangles and introns as crooked lines. Note: the exon/intron lengths on these gene diagrams are not to scale. C. The pathway in which PANK participates is universal, involving the phosphorylation of pantothenate as a rate-determining step in the formation of Coenzyme A (CoA). In turn, CoA participates in many metabolic and other biochemical reactions in all known biological species.

Figure 3

MiR-103/107 show an unusual tendency to target mRNAs in the lipid and pyruvate metabolic pathways. This chart relates six different human brain-enriched miRNAs (columns) to metabolism-related “target mRNAs” (rows) with predictions from different databases as to which miRNAs are predicted to target which mRNAs (shaded rectangles). The top left portion of the chart shows the four different databases that were used (see references in text). The numbers 1–4 are also used in the chart to indicate which database(s) predicted each highlighted miRNA/mRNA pair: (1) MiRANDA, 2005 build via MSKCC: http://cbio.mskcc.org/cgi-bin/mirnaviewer/mirnaviewer.pl (2) MiRANDA, 2006 build via Sanger: http://microrna.sanger.ac.uk/cgi-bin/targets/v4/hit_list.pl? (3) PicTar: http://pictar.bio.nyu.edu/ (4) TargetScan 2006 build: http://www.targetscan.org/mamm_30/

Figure 4

MiR-103/107 and PANKs may constitute coordinated transcription units with synergistic cellular effects concerning cellular acetyl-CoA levels and other metabolic pathway elements. A. A diagram shows a metabolic pathway that has been previously determined, along with some of the metabolic nodes which are predicted to be inhibited (red) or stimulated (green; through decrease of inhibitory targets) by miR-103/7. MiR-107 may be stimulated coordinately with PANK1. B. Like PANKs, miR-103/7 may function to increase cellular acetyl-CoA levels, and miR-103/7 may also inhibit the synthesis and metabolism of cellular lipids.