Genetics-driven discovery of novel regulators of lipid metabolism

Abstract

Purpose of review: Residual cardiovascular disease risk and increasing metabolic syndrome risk underscores a need for novel therapeutics targeting lipid metabolism in humans. Unbiased human genetic screens have proven powerful in identifying novel genomic loci, and this review discusses recent developments in such discovery. Recent findings: Recent human genome-wide association studies have been completed in incredibly large, detailed cohorts, allowing for the identification of >300 genomic loci that participate in regulation of plasma lipid metabolism. However, the discovery of these loci has greatly outpaced the elucidation of the underlying functional mechanisms. The identification of novel roles for long noncoding RNAs such as CHROME, LeXis, and MeXis, in lipid metabolism suggests that noncoding RNAs should be included in functional translation of GWAS loci. Summary: Unbiased genetic studies appear to have unearthed a great deal of novel biology with respect to lipid metabolism, yet translation of these findings into actionable mechanisms has been slow. Increased focus on the translation, rather than the discovery, of these loci, with new attention paid to lncRNAs, can help spur the development of novel therapeutics targeting lipid metabolism.

Genética del metabolismo lipídico en la biología del desarrollo de la aterosclerosis

“…Comprender la biología del metabolismo de los lípidos ha recibido mucha atención debido a la importancia de los lípidos para la salud metabólica. Donde, análisis genéticos imparciales, como los estudios de asociación del genoma completo, han demostrado ser increíblemente efectivos para descubrir nuevas regiones del genoma asociadas con la patogenia de la enfermedad arterial coronaria, dislipidemia y aterosclerosis (35).…”

Potential therapeutic targeting of lncRNAs in cholesterol homeostasis

“…Hepatic overexpression of LeXis in mice decreased plasma cholesterol, whereas LeXis knockout mice had the opposite phenotype of increased serum cholesterol level and upregulated cholesterol biosynthetic gene expression [35]. Raising or lowering LeXis levels in the liver and plasma affected cholesterol biosynthesis and altered the cholesterol levels by LXRs activation.…”

Potential Therapeutic Targeting of lncRNAs in Cholesterol Homeostasis

“…LeXis is a lipid-responsive lncRNA, highly expressed in the hepatic tissue and robustly induced by Western diet (high in fat and cholesterol) and pharmacologic liver X receptors (LXRs) activation ( 46 ). Hepatic overexpression of LeXis in mice decreased plasma cholesterol, whereas LeXis knockout mice had the opposite phenotype of increased serum cholesterol level and upregulated cholesterol biosynthetic gene expression ( 67 ). Raising or lowering LeXis levels in the liver and plasma affected cholesterol biosynthesis and altered the cholesterol levels by LXRs activation.…”