Abstract
High-density lipoproteins play a central role in systemic cholesterol homeostasis by stimulating the efflux of excess cellular cholesterol and transporting it to the liver for biliary excretion. HDL has long been touted as the "good cholesterol" because of the strong inverse correlation of plasma HDL cholesterol levels with coronary heart disease. However, the disappointing outcomes of recent clinical trials involving therapeutic elevations of HDL cholesterol have called this moniker into question and revealed our lack of understanding of this complex lipoprotein. At the same time, the discovery of microRNAs (miRNAs) that regulate HDL biogenesis and function have led to a surge in our understanding of the posttranscriptional mechanisms regulating plasma levels of HDL. Furthermore, HDL has recently been shown to selectively transport miRNAs and thereby facilitate cellular communication by shuttling these potent gene regulators to distal tissues. Finally, that miRNA cargo carried by HDL may be altered during disease states further broadened our perspective of how this lipoprotein can have complex effects on target cells and tissues. The unraveling of how these tiny RNAs govern HDL metabolism and contribute to its actions promises to reveal new therapeutic strategies to optimize cardiovascular health.
Highlights
High-density lipoproteins play a central role in systemic cholesterol homeostasis by stimulating the efflux of excess cellular cholesterol and transporting it to the liver for biliary excretion
These studies paved the way for the first experiments of miRNA targeting in nonhuman primates, which showed that silencing of miR-122 using locked nucleic acid (LNA) antagomirs in African green monkeys [25] and chimpanzees [26] caused substantial reductions in total plasma cholesterol, with no apparent toxicity or histopathological changes in the liver
Recent studies have suggested that the vascular effects of high density lipoprotein (HDL), including regulation of endothelial nitric oxide, anti-oxidative, anti-inflammatory, and anti-thrombotic functions, can be highly heterogenous, and that HDL may become altered in patients with cardiovascular disease (CVD) or diabetes [46]
Summary
Cholesterol and fatty acid synthesis, plasma cholesterol, hepatatis C virus accumulation. Numerous genes involved in cholesterol and fatty acid biosynthesis and metabolism were altered by anti-miR-122 treatment despite a lack of miR-122 binding sites in their 3′UTR, suggesting that their regulation resulted from secondary effects on miR-122 targets in the liver. These studies paved the way for the first experiments of miRNA targeting in nonhuman primates, which showed that silencing of miR-122 using locked nucleic acid (LNA) antagomirs in African green monkeys [25] and chimpanzees [26] caused substantial reductions in total plasma cholesterol, with no apparent toxicity or histopathological changes in the liver. Such studies will provide insight into whether SR-BI-targeting miRNAs hold potential as therapeutic targets to increase hepatic SR-BI expression, and enhance selective cholesteryl ester uptake and RCT
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