| Deregulated lipid homeostasis is associated with the development of many disorders, including atherosclerosis, complications from which are the leading cause of death worldwide. Among the cardinal features of this disease, an elevated low-density lipoprotein/high-density lipoprotein-cholesterol (LDL/HDL-C) ratio is unique in being sufficient to drive its development. As such, substantial therapeutic progress has resulted from the widespread use of statins and other lipid-lowering drugs aimed at lowering LDL-C. Despite this, statins are not sufficient to prevent cardiovascular disease (CVD) in many individuals and therefore, there is increased interest in targeting other lipid-related risk factors to treat cardiometabolic disorders.;Recently, microRNAs (miRNAs), a class of short non-coding RNAs that modulate mRNA translation and turnover, have been implicated in the control of metabolic homeostasis. Of note, our group identified microRNA-33a/b (miR-33a/b), intronic miRNAs located within the sterol regulatory element-binding protein (SREBP) genes, as master regulators of lipid metabolism through the coordinated control of cholesterol biosynthesis, cholesterol efflux, and HDL biogenesis. In addition, the work presented herein implicates miR-33a/b as key regulators of fatty acid metabolism and insulin signaling. Moreover, our work also supports a regulatory role for the passenger strand of miR-33, miR-33*, and suggests that miR-33 regulates lipid metabolism through both arms of the miR-33/33* duplex. Thus, miR-33/33* may be useful as a therapeutic targets to treat major components of metabolic syndrome, namely high triglycerides, low HDL-C levels and insulin resistance.;Previous studies have demonstrated that short-term antagonism of miR-33 in vivo increases circulating HDL-C and reverse cholesterol transport (RCT), thereby reducing the progression and increasing the regression of atherosclerosis. Here, we show that long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and lipid accumulation in the livers of mice fed a high fat diet (HFD). Mechanistically, we demonstrate that chronic inhibition of miR-33 increases genes involved in fatty acid synthesis, possibly through the enhanced expression of NFYC, a transcriptional regulator required for SREBP activation. These unexpected findings demonstrate that long-term inhibition of miR-33 in HFD-fed mice may cause deleterious effects, such as moderate hepatic steatosis and hypertriglyceridemia and emphasize the importance of assessing anti-miR-33 treatment in non-human primates before this therapy is translated to humans.;While these studies highlight the therapeutic potential of manipulating miRNAs to control HDL-C levels, the effect of miRNAs on hepatic LDL receptor (LDLR) activity, the main factor for controlling levels of plasma LDL-C, has not yet been well described. As such, here, we also set out to identify novel miRNAs that regulate LDLR activity in human hepatic cells using a high-throughput genome-wide miRNA screen. From this screen, we characterized miR-148a as a negative regulator of LDLR expression and activity and defined a novel SREBP1-mediated pathway by which miR-148a regulates LDL-C uptake. Importantly, inhibition of miR-148a increased hepatic LDLR expression and decreased plasma LDL-C in vivo. We also provide evidence that miR-148a regulates hepatic ABCA1 expression and circulating HDL-C levels, thereby identifying miR-148a as a potential therapeutic target to simultaneously lower LDL-C and increase HDL-C levels. Collectively, these studies demonstrate that miR-33 and miR-148a are critical components of the cholesterol regulatory circuitry and highlight miRNAs as viable therapeutic targets for the treatment of atherosclerosis and related CVDs. |
