Abstract
ABSTRACT Hypercholesterolemia is a strong predictor of cardiovascular diseases that result in the largest number of mortality and morbidity worldwide. 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. Here, we show that Hmgcr is markedly inhibited, while miR-27a is highly induced in various cultured cell lines, human tissues as well as several rodent models of metabolic disorders (viz. genetically hypertensive blood pressure high mice, spontaneously hypertensive rats and high fat and high fructose diet-fed rats). Our in vitro data shows that miR-27a specifically interacts with the 3’-untranslated region of Hmgcr in murine and human hepatocytes. Our actinomycin D chase experiments demonstrate that miR-27a regulates Hmgcr by translational attenuation rather than mRNA degradation. Moreover, systematic in silico and functional analyses reveal that miR-27a expression is modulated by intracellular cholesterol level via Early Growth Response 1 transcription factor. Augmentation of miR-27a expression abrogates hyperlipidemia/atherosclerosis and improves cardiac function in high cholesterol diet-fed Apoe-/- mice. Pathway and gene expression analyses reveal that miR-27a also targets other genes (apart from Hmgcr) involved in cholesterol homeostasis. Our results suggest miR-27a as an attractive therapeutic candidate for clinical management of hypercholesterolemia and atherosclerosis.
SIGNIFICANCE STATEMENT Elevated cholesterol level is an important risk factor for cardiovascular diseases. 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) is the rate-limiting enzyme in cholesterol biosynthesis pathway. Presently, statins (Hmgcr inhibitors) are used to lower the risk of cardiovascular complications by controlling the cholesterol level. However, statins show variable effects including serious adverse reactions in some patients. This work identifies microRNA-27a (miR-27a) as a crucial regulator of cholesterol biosynthesis as it targets many cholesterol regulatory genes including Hmgcr. We also demonstrate the efficacy of miR-27a in improving cardiac function and alleviating atherosclerosis. Taken together, this study highlights the role of miR-27a in cholesterol regulation and provides a potential therapeutic candidate to treat elevated cholesterol level and atherosclerosis.
Footnotes
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