Proper maintenance of cellular and plasma cholesterol levels is critical for proper metabolic function and as such is regulated through tightly controlled mechanisms at both the transcriptional and posttranscriptional level. Cardiometabolic diseases, including atherosclerosis, a prominent cause of human morbidity and mortality in western societies (Glass and Witztum 2001; Lusis 2000), are caused in large part by dysregulation of cholesterol and lipid homeostasis. Although many environmental and genetic factors are known to contribute to atherogenesis, elevated levels of low-density lipoprotein cholesterol (LDL-C) are the primary risk factors for atherosclerosis and are sufficient to drive the progression of this disease. For this reason, the pathways governing plasma LDL-C levels have been extensively studied, and their modulation has led to effective therapies for the treatment of atherosclerosis.
The primary treatment option for patients with hypercholesterolemia is statins, a class of drugs which competitively inhibit 3-hydroxy-3methylgutaryl-CoA reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthesis pathway (Steinberg 2008; Steinberg et al. 2008). Reduced intracellular cholesterol synthesis in the liver, in response to statins, leads to activation of the sterol regulatory elementbinding protein (SREBP), which increases the expression of the LDL receptor (LDLR). This in turn promotes LDL-C uptake from the blood and reduces levels of pro-atherogenic lipoproteins in circulation (Brown and Goldstein 1976). Although statin therapies have proven to be effective at reducing cholesterol levels and limiting cardiovascular-related deaths, some patients have poor tolerance for statin therapies, and the majority of patients still experience adverse coronary events despite treatment with statins (Steinberg 2008; Steinberg et al. 2008). As a result, developing novel approaches for lowering cholesterol that can be used alone or in combination with statins has become a major goal for cardiovascular research. Among these, approaches that modulate noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), have generated a great deal of interest due to their ability to regulate key pathways in cholesterol metabolism and their dysregula- tion in different disease states (Grundy 2008; Grundy et al. 2004). In this review, we highlight recent work demonstrating the importance of miRNAs and lncRNAs in regulation of cholesterol metabolism and discuss the potential of noncoding RNA- based therapeutic approaches for the treatment of atherosclerosis.
- 2 Noncoding RNAs in Cholesterol Metabolism and Atherosclerosis