Regulation of cholesterol/lipid homeostasis by microRNA-33a/b

描述(由申请者提供)：准确调节胆固醇/脂类稳态对人类健康至关重要。事实上，高循环低密度脂蛋白/高密度脂蛋白比率和甘油三酯升高与代谢综合征、II型糖尿病和心血管疾病(CVD)相关。对高密度脂蛋白和甘油三酯循环水平调节机制的更好理解可能会产生对抗心脏代谢障碍的新的治疗途径。我们最近有了一个令人惊讶的发现，编码胆固醇/脂类生物合成关键转录调节因子的人类SREBP-1和-2基因含有内含子microRNAs(分别为miR-33b和miR-33a)。有趣的是，miR-33a/b是ABCA1胆固醇转运蛋白和高密度脂蛋白合成的关键抑制剂，可以提高细胞内胆固醇水平，而注射针对miR-33a的反义寡核苷酸显著提高了西式饮食小鼠的高密度脂蛋白水平。我们在这里建议检验这一假设，即miR-33a/b代表哺乳动物胆固醇/脂代谢的多个方面的中央调节因子，与SREBP宿主基因密切合作。无论是体外细胞培养还是在小鼠和非人类灵长类动物身上的体内研究，都将为miR-33a/b在靶向引导脂质和能量稳态的整个通路中的作用以及miR-33a/b是否适合用于代谢综合征患者提高循环高密度脂蛋白和降低血浆甘油三酯的靶向治疗提供关键的机制见解。

DESCRIPTION (provided by applicant): Accurate regulation of cholesterol/lipid homeostasis is essential to human health. Indeed, high circulating LDL- to-HDL ratios and elevated triglycerides are associated with metabolic syndrome, type II diabetes, and cardiovascular disease (CVD). An improved understanding of the regulatory mechanisms governing circulating levels of HDL and triglycerides could yield novel therapeutic avenues to combat cardiometabolic disorders. We recently made the surprising discovery that the human SREBP-1 and -2 genes encoding key transcriptional regulators of cholesterol/lipid biosynthesis harbor intronic microRNAs (miR-33b and miR-33a, respectively). Intriguingly, miR-33a/b represent key inhibitors of the ABCA1 cholesterol transporter and HDL synthesis to boost intracellular cholesterol levels, and injection of antisense oligonucleotides directed against miR-33a significantly increases HDL levels in mice on a western-type diet. We propose here to test the hypothesis that miR-33a/b represent central regulators of multiple aspects of mammalian cholesterol/lipid metabolism, in close cooperation with the SREBP host genes. Both in vitro cell culture and in vivo studies in mice and non-human primates will provide key mechanistic insights into the role of miR-33a/b in targeting entire pathways guiding lipid and energy homeostasis, and whether miR-33a/b may be suitable for therapeutic targeting to raise circulating HDL and lower plasma triglycerides in metabolic syndrome patients.