| The discovery of microRNAs as key regulators of cellular homeostasis has unlocked promising approaches for the management of human disease. Cardiovascular disease, the cause of death for nearly 30% of Americans, is among the many diseases that could benefit from novel therapies. A common therapeutic goal for managing cardiovascular disease risk is the correction of dyslipidemias, primary risk factors for atherosclerosis. Specifically, therapies that increase the flow of cholesterol out of the body through the reverse cholesterol transport (RCT) pathway are thought to be athero-protective. The work presented herein identifies microRNA-33 (miR-33) as both a master regulator of sterol and lipoprotein metabolism and a potential novel therapeutic target for the treatment of cardiovascular disease. miR-33 was found to be co-expressed with its host gene, SREBP-2, in response to low intracellular cholesterol, or, in response to statin drugs. Induction of miR-33 promoted the repression of its target genes, several of which have been implicated in the RCT pathway. These included the cholesterol efflux proteins ABCA1 and ABCG1 and the hepatocyte canalicular transporters ABCB11 and ATP8B1. Importantly, our work showed that silencing of miR-33 in mice with antisense oligonucleotides (ASOs) promoted increased high-density lipoprotein cholesterol, increased biliary secretion, and enhanced flow of cholesterol through the RCT pathway. Additionally, our work identified miR-33 as a likely mediator of statin-induced hepatotoxicity and cholestasis. Taken together, our results strongly supported the development of miR-33 ASOs to prevent or treat atherosclerosis, as well as drug-induced cholestasis in humans.;However, multiple labs have reported conflicting results on the effectiveness of miR-33 ASOs to alter the progression of atherosclerosis in mice. Our research identified N-ethylmaleimide sensitive factor (NSF) as a novel functional target gene of miR-33 that modulates the secretion of very-low density lipoprotein (VLDL). Hence, silencing miR-33 raised hepatic NSF expression and increased VLDL secretion in mice. As VLDL secretion is the precursor for atherogenic LDL-C, we speculated that miR-33-mediated regulation of NSF might compromise the therapeutic value of miR-33 ASOs in patients at risk for cardiovascular disease. Collectively, our work provides a cautionary example for microRNA-based development of drug therapies. |
