Long Non-coding RNA Reduces Arteriosclerosis Risk

A gene has been identified that produces a long non-coding RNA, which has been linked to the maintenance of cellular cholesterol balance and the development of arteriosclerosis.

Long non-coding RNAs (lncRNAs) are considered to be non-protein coding transcripts longer than 200 nucleotides. This somewhat arbitrary limit distinguishes lncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. LncRNAs have been found to be involved in numerous biological roles including imprinting, epigenetic gene regulation, cell cycle and apoptosis, and metastasis and prognosis in solid tumors. Most lncRNAs are expressed only in a few cells rather than whole tissues, or they are expressed at very low levels, making them difficult to study. Their name notwithstanding, long non-coding RNAs (lncRNAs) have been found to actually encode synthesis of small polypeptides that can fine-tune the activity of critical cellular components.

Investigators at the University of California, Los Angeles (USA) have outlined a role for an lncRNA in modulating the cell type-specific actions of liver X receptors (LXRs). These are sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis that have been causally linked to the pathogenesis of atherosclerosis.

The investigators reported in the February 12, 2018, online edition of the journal Nature Medicine that the lncRNA, MeXis, acted as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux. Mice lacking the gene for MeXis production showed reduced Abca1 expression in a tissue-selective manner. Furthermore, loss of MeXis in mouse bone marrow cells altered chromosome architecture at the Abca1 locus, impaired cellular responses to cholesterol overload, and accelerated the development of atherosclerosis. Mice lacking MeXis had almost twice as many blockages in their blood vessels compared to mice with normal MeXis levels. Furthermore, elevated MeXis levels improved the cells ability to remove excess cholesterol.

"What this study tells us is that lncRNAs are important for the inner workings of cells involved in the development of heart disease," said senior author Dr. Peter Tontonoz, professor of pathology and laboratory medicine at the University of California, Los Angeles. "Considering many genes like MeXis have completely unknown functions, our study suggests that further exploring how other long non-coding RNAs act will lead to exciting insights into both normal physiology and disease."

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