Editors' ChoiceCardiovascular Disease

A lncRNA that regulates cholesterol homeostasis

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Science Translational Medicine  19 Dec 2018:
Vol. 10, Issue 472, eaaw0526
DOI: 10.1126/scitranslmed.aaw0526

Abstract

The primate-specific long noncoding RNA CHROME regulates cholesterol metabolism through its interaction with specific microRNAs.

Hypercholesterolemia is one of the prime risk factors for the development of cardiovascular disease. Hence, it is not surprising that many molecular and biochemical pathways exist to maintain healthy blood cholesterol concentrations. This regulation includes transcriptional responses, for instance through the so-called LXR transcription factors, but also posttranscriptional regulation, for instance through posttranslational modifications. Another mode of posttranscriptional regulation is through noncoding RNAs, but little is known about the extent of noncoding RNAs in cholesterol management.

Hennessy and colleagues identified a long noncoding RNA (lncRNA), called CHROME, which is important for cholesterol homeostasis. CHROME is a primate-specific lncRNA and is highly expressed in atherosclerotic plaques. Moreover, its expression in the liver—a tissue that is crucial for cholesterol homeostasis—is strongly induced upon several weeks of dietary cholesterol consumption, and this induction is dependent on the LXR transcription factor. This suggests that CHROME may have a physiological role in conditions of excess dietary cholesterol, in a manner that is closely linked to other regulatory networks managing plasma cholesterol.

The authors went on to identify how CHROME achieves its action. LncRNAs are RNA molecules of >200 nucleotides that don’t code for protein. Although many lncRNAs are not well conserved across species, they can modulate gene and protein expression in many ways, for example by binding other RNAs such as microRNAs. Indeed, the authors found CHROME bound to four specific microRNAs that were previously linked to cholesterol metabolism. Reducing the expression of CHROME in hepatocytes increased the expression of these microRNAs. Functionally, this concerted action led to repressed expression of a variety of target genes involved in cholesterol homeostasis. Conversely, CHROME overexpression reduced expression of the same four specific microRNAs, with a concurrent increase of cholesterol-regulating target genes and cholesterol efflux from the cells.

More work is required to understand the intricacies of how CHROME, or lncRNAs in general, modulate the highly regulated metabolic network of cholesterol homeostasis, and whether this can be targeted as a lipid-lowering therapy. However, the identification of CHROME as a lncRNA in primates is an important step in the quest to understand cholesterol homeostasis and work toward treating cardiovascular disease.

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