MicroRNA 27a Is a Key Modulator of Cholesterol Biosynthesis

Abstract

Hypercholesterolemia is a strong predictor of cardiovascular diseases. The 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 posttranscriptional regulation of Hmgcr remains poorly understood. The main objective of this study was to explore the role of microRNAs (miRNAs) in the regulation of Hmgcr expression. Systematic in silico predictions and experimental analyses reveal that miRNA 27a (miR-27a) specifically interacts with the Hmgcr 3′ untranslated region in murine and human hepatocytes. Moreover, our data show that Hmgcr expression is inversely correlated with miR-27a levels in various cultured cell lines and in 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 downregulation 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 the cholesterol biosynthesis pathway. Taken together, miR-27a emerges as a key regulator of cholesterol biosynthesis and has therapeutic potential for the clinical management of hypercholesterolemia.

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“…3 A and Additional file 1 : S2A). In some cases, two bands of HMGCR have been detected in our and other studies [ 32 , 33 ]. The upper one is the HMGCR band and the lower one is the non-specific band.…”

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“…Moreover, it was observed that hypoxia, a sign of liver damage, induced binding of early growth response protein 1 (Egr1) to promoter regions of miR-27a, leading to its induction, to mediate the downregulation of HMGCR. Finally, increase of miR-27a and decrease of HMGCR were found in livers of three mice models of MetS [334]. Further, C57BL/6J mice with diet-induced hypercholesterolemia showed also amelioration of hypercholesterolemia, yet upon delivery of miR-30c mimic to the liver due to decrease of hepatic lipoprotein production but not LDL clearance [335].…”

“…Other miRNAs implicated in potential therapy of hypercholesterolemia are miR-27a and miR-30c. First of them was injected via tail vein into Apoe-/-mice subjected to high cholesterol diet and suggested to diminish plasma lipid levels along with hepatic levels of HMGCR [334]. Further, miR-27a was proved to directly target HMGCR via translational repression and mRNA decay.…”

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“…miRNA-122, present mainly in hepatocytes, when inhibited significantly suppresses blood cholesterol level ( Rotllan and Fernandez-Hernando, 2012 ). miR-27a has been shown to control HMGCR level either by a posttranslational block or by mRNA degradation ( Khan et al, 2020 ). Strikingly, other miRNAs have been discovered by meta-analyses to be associated with cholesterol–lipoprotein trafficking alterations, such as miR-128-1, miR-148a, miR-130b, and miR-301b.…”

“…miR-27a has been shown to control HMGCR level either by a posttranslational block or by mRNA degradation (Khan et al, 2020). Strikingly, other miRNAs have been discovered by meta-analyses to be associated with cholesterol-lipoprotein trafficking alterations, such as miR-128-1, miR-148a, miR-130b, and miR-301b.…”