Key Points
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MicroRNAs (miRNAs) such as miR-33a and miR-33b are key regulators of cholesterol and lipid homeostasis and represent attractive therapeutic targets for raising high-density lipoprotein (HDL) levels and lowering triglyceride levels.
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A role has recently been elucidated for miRNAs (for example, miR-103, miR-107 and let-7) in regulation of insulin signalling and control of glucose homeostasis.
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An emerging link of certain miRNAs to metabolic dysregulation in adipogenesis and obesity suggests that this class of non-coding RNAs may have important roles in disorders associated with metabolic syndrome (MetS).
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Aberrant hepatic miRNA expression may also contribute to other aspects of MetS, such as non-alcoholic fatty liver disease (NAFLD).
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Circulating miRNAs have recently been identified in the blood, including as part of HDL. Data suggest that circulating miRNAs may exert effects on gene expression in target cells and tissues.
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The link of abnormal miRNA expression to metabolic disorders has highlighted the therapeutic potential of antisense targeting of specific miRNAs (for example, miR-122, miR-33a and miR-33b).
Abstract
MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. For example, miR-33a and miR-33b have a crucial role in controlling cholesterol and lipid metabolism in concert with their host genes, the sterol-regulatory element-binding protein (SREBP) transcription factors. Other metabolic miRNAs, such as miR-103 and miR-107, regulate insulin and glucose homeostasis, whereas miRNAs such as miR-34a are emerging as key regulators of hepatic lipid homeostasis. The discovery of circulating miRNAs has highlighted their potential as both endocrine signalling molecules and disease markers. Dysregulation of miRNAs may contribute to metabolic abnormalities, suggesting that miRNAs may potentially serve as therapeutic targets for ameliorating cardiometabolic disorders.
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Change history
26 March 2012
On page 250 of this article, the competing financial interests statement incorrectly stated that the authors had no competing interests. The authors' statement is reproduced below, and the article has been corrected online. The editors apologize for this omission.
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Acknowledgements
This work was supported by US National Institutes of Health (NIH) grants R21DK084459 and R01DK094184. The authors apologize for their inability to discuss and cite all relevant papers owing to space constraints.
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Anders M. Näär has patents pending on miR-33a and miR-33b antisense targeting for the treatment of cardiometabolic disorders. These patents have been licensed by Santaris Pharma, Denmark. Veerle Rottiers declares no competing financial interests.
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Distict cytoplasmic foci that contain a number of enzymes involved in mRNA turnover. They are important for mRNA degradation, storage of mRNA for translation and translational repression by microRNAs.
- Metabolic syndrome
-
(MetS). A combination of metabolic disorders characterized by insulin resistance, obesity, abnormalities in circulating cholesterol and lipid profiles, non-alcoholic fatty liver disease and hypertension. MetS is associated with increased risk of type 2 diabetes and cardiovascular disease (coronary artery disease and stroke).
- Endocrine signalling
-
Hormonal signal, secreted from a specific cell and causing a specific effect in distal target cells. Hormones produced by endocrine cells can travel through the blood to reach all parts of the body.
- Triglycerides
-
Esters of glycerol and fatty acids, used for the storage of energy.
- Antagomirs
-
Small, synthetic, cholesterol-conjugated DNA oligonucleotides that are complementary to an endogenous microRNA (miRNA) of interest. The cholesterol moiety allows antagomirs to enter most cell types efficiently, where they specifically bind and sequester endogenous miRNAs.
- Fatty acid β-oxidation
-
Degradation process of fatty acids to acetyl-CoA primarily in the mitochondria. Long chain fatty acids need to be transported via binding to carnitine.
- Locked nucleic acid
-
(LNA). A modified DNA oligonucleotide analogue that is locked in an 'N-type conformation'. LNA is capable of recognizing DNA and RNA with high affinity and is resistant to degradation.
- Apolipoprotein A1
-
(APOA1). The major protein component of high-density lipoprotein (HDL) in plasma. It promotes the efflux of cholesterol from tissues to the liver, and defects cause low HDL levels, which are often associated with cardiovascular disease.
- Atherogenic macrophages
-
Cholesterol-loaded macrophages that accumulate in the arterial wall and can lead to atherosclerotic lesions.
- Lipid raft
-
Microdomain of the cell plasma membrane with high cholesterol and sphingolipid content that compartmentalizes cellular processes by acting as a platform to colocalize proteins such as signalling molecules and receptors.
- Exosomes
-
Small (30–90 nm) vesicles secreted from the plasma membrane of mammalian cells. They contain proteins, RNA and microRNA molecules and can be transported from cell to cell.
- Paracrine signalling
-
Signalling mediated by secreted molecules that act locally.
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Rottiers, V., Näär, A. MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol 13, 239–250 (2012). https://doi.org/10.1038/nrm3313
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DOI: https://doi.org/10.1038/nrm3313
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