Tontonoz’s group has recently identified liver-expressed LXR-induced sequence (LeXis), a liver noncoding RNA that is markedly induced in response to LXR agonists and high-fat diet (Sallam et al. 2016). Hepatic LeXis overexpression reduces circulating cholesterol, attenuates cholesterol biosynthesis, and inhibits the expression of cholesterol biosynthetic genes. Conversely, genetic ablation of LeXis or acute pharmacological inhibition using ASOs enhances the hepatic expression of genes associated with cholesterol biosynthesis, leading to a significant accumulation of cholesterol in the liver. Mechanistically, the authors found that LeXis interacts with and influences the binding of RALY to DNA. The authors hypothesize that RALY might cooperate with SREBP2 to control the expression of cholesterol biosynthetic genes. However, further studies are needed to support this hypothesis. Another important question that remains to be addressed is the study of the contribution of LeXis in regulating cholesterol metabolism in humans. Importantly, mouse and human genomic comparison revealed a moderate conservation on the LeXis genetic locus in a region adjacent to the human ABCA1 gene.

Further experiments are warranted to determine whether the putative lncRNA annotated in this region (TCONS_00016452) regulates cholesterol metabolism in humans.

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