MicroRNA-27a is a key modulator of cholesterol biosynthesis

Abstract

Hypercholesterolemia is a strong predictor of cardiovascular diseases. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase gene (Hmgcr) coding for the rate-limiting enzyme in the cholesterol biosynthesis pathway is a crucial regulator of plasma cholesterol levels. However, the post-transcriptional regulation of Hmgcr remains poorly understood. The main objective of this study was to explore the role of miRNAs in the regulation of Hmgcr expression. Systematic in silico predictions and experimental analyses reveal that miR-27a specifically interacts with the Hmgcr 3-untranslated region in murine and human hepatocytes. Moreover, our data shows that Hmgcr expression is inversely correlated with miR-27a levels in various cultured cell lines, human and rodent tissues. Actinomycin D chase assays and relevant experiments demonstrate that miR-27a regulates Hmgcr by translational attenuation followed by mRNA degradation. Early Growth Response 1 (Egr1) regulates miR-27a expression under basal and cholesterol-modulated conditions. miR-27a augmentation via tail-vein injection of miR-27a mimic in high cholesterol diet-fed Apoe-/- mice shows down-regulation of hepatic Hmgcr and plasma cholesterol levels. Pathway and gene expression analyses show that miR-27a also targets several other genes (apart from Hmgcr) in cholesterol biosynthesis pathway. Taken together, miR-27a emerges as a key regulator of cholesterol biosynthesis and has therapeutic potential for clinical management of hypercholesterolemia.