Abstract
Disruption of cellular cholesterol balance results in pathologic processes including atherosclerosis, metabolic syndrome, type II diabetes and Alzheimer's disease. Maintenance of cholesterol homeostasis requires constant metabolic adjustment, achieved partly through the fine regulation of the classical transcription factors (e.g., by SREBP and LXR), but also through members of a class of noncoding RNAs termed miRNAs. Some miRNAs have now been identified to be potent post-transcriptional regulators of lipid metabolism genes, including miR-122, miR-33, miR-758, and miR-106b. Different strategies have been developed to modulate miRNA effects for therapeutic purposes. The promise demonstrated by the use of anti-miRs in human preclinical studies, in the case of miR-122, raises the possibility that miR-33, miR-758, and miR-106b may become viable therapeutic targets in future. This review summarizes the evidence for a critical role of some miRNAs in regulating cholesterol metabolism and suggests novel ways to manage dyslipidemias and cardiovascular diseases.
Highlights
Cholesterol is the major component of mammalian cells and is essential for diverse cellular functions
A role for miR-122 in lipid metabolism was revealed in knockdown studies [11, 23]. miR-122 inhibition by antisense oligonucleotides (ASO) in mice resulted in increased hepatic fatty-acid oxidation and a reduced cholesterol synthesis [23]
Neuro2a cells transfected with miR-106b dramatically increase levels of secreted Aβ by increasing Aβ production and preventing Aβ clearance [14]. These findings suggest an important role for miR-758 and miR106b in regulating neurological functions and might have important implications in the pathogenesis of Alzheimer’s disease (AD) through posttranscriptional repression of ATP binding cassette transporters A1 (ABCA1)
Summary
Cholesterol is the major component of mammalian cells and is essential for diverse cellular functions. In addition to the classical transcriptional regulators, a class of noncoding RNAs, termed microRNAs (miRNAs) has emerged as critical regulators of gene expression acting predominantly at the posttranscriptional level. This large family of short (22-nucleotide) noncoding RNA binds to the 3 untranslated (3 UTR) region of mRNA, thereby repressing gene expression. They are implicated in the control of many physiological and pathological processes [8,9,10]. This paper addresses recent research and links between miRNAs and their role in regulating cholesterol metabolism and suggests that manipulating their expression in vivo may open new avenues for treating dyslipidemias and cardiovascular diseases
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