Editors' ChoiceCholesterol Metabolism

LXR maintains cholesterol balance through a noncoding RNA

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Sci. Signal.  07 Jun 2016:
Vol. 9, Issue 431, pp. ec133
DOI: 10.1126/scisignal.aag2817

Liver X receptors (LXRs) are nuclear receptors that mediate adaptive responses to excess cholesterol. When bound to cholesterol derivatives (oxysterols), LXRs stimulate the expression of genes that inhibit cholesterol uptake and genes that promote cholesterol efflux and fatty acid synthesis. Sallam et al. found that feeding mice a Western (high fat, high cholesterol) diet or the synthetic LXR agonist GW3965 also inhibited the expression of genes involved in cholesterol biosynthesis and stimulated expression of the predicted noncoding RNA LeXis (liver-expressed LXR-induced sequence) in the liver and in several other tissues. Treatment of primary hepatocytes with GW3965 induced LeXis expression in a manner that depended on the presence of either LXRα or LXRβ, and chromatin immuoprecipitation assays demonstrated that LeXis was a direct LXR target. In vivo experiments in which LeXis was overexpressed, knocked down, or knocked out indicated that LeXis reduced both serum and hepatic cholesterol, inhibited the expression of cholesterol biosynthesis genes, and reduced the accumulation of lipids in the livers of mice fed a Western diet. Pull-down assays and coimmunoprecipitation experiments showed that LeXis interacted with the heterogeneous ribonucleoprotein RALY. RALY contains both an RNA-binding domain and a leucine zipper, suggesting that it may interact with DNA in a manner that is regulated by RNA binding. In vivo experiments were consistent with RALY acting as a transcriptional cofactor for genes involved in cholesterol biosynthesis. RALY bound to the promoters of cholesterol biosynthesis genes in the liver, and LeXis overexpression reduced this binding. Thus, LXR activity controls all aspects of cellular cholesterol homeostasis—inhibits cholesterol uptake, promotes cholesterol efflux, promotes cholesterol conversion to fatty acids, and limits cholesterol biosynthesis—through a combination of direct transcriptional regulation and indirect regulation through LeXis.

T. Sallam, M. C. Jones, T. Gilliland, L. Zhang, X. Wu, A. Eskin, J. Sandhu, D. Casero, T. Q. de Aguiar Vallim, C. Hong, M. Katz, R. Lee, J. Whitelegge, P. Tontonoz, Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature 534, 124–128 (2016). [PubMed]