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

microRNA-33a/b 调节胆固醇/脂质稳态

基本信息

批准号：
8337383
负责人：
ANDERS M NAAR
金额：
$ 68.6万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-24 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337383
关键词：
3&apos Untranslated Regions ADD-1 protein Address Affect Antisense Oligonucleotides Binding Proteins Biological Assay Cardiovascular Diseases Cell Culture Techniques Cells Cercopithecus pygerythrus Cholesterol Cholesterol Homeostasis Code Cues DNA Microarray Chip Data Diet Disease Enzymes Fatty Acids Feedback Gene Expression Gene Proteins Genes Genome Glucose HDL-triglyceride Health High Density Lipoproteins Homeostasis Human Hypertriglyceridemia In Vitro Individual Injection of therapeutic agent Insulin Insulin Resistance Light Lipids Liver Low-Density Lipoproteins Mediating Metabolic Metabolic Control Metabolic syndrome MicroRNAs Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Oligonucleotides Pathway interactions Patients Plasma Production Protein Family Regulation Regulatory Element Role SRE-1 binding protein Signal Transduction Sterols Stress Testing Therapeutic Translations Triglycerides adenylate kinase base cholesterol control cholesterol transporters combat design feeding improved in vivo inhibitor/antagonist insight lipid biosynthesis lipid metabolism lipoprotein triglyceride member nonhuman primate novel strategies novel therapeutics oxidation protein function response sensor therapeutic target trafficking transcription factor

项目摘要

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.

描述（由申请人提供）：胆固醇/脂质稳态的准确调节对于人类健康至关重要。事实上，高循环 LDL-HDL 比率和升高的甘油三酯与代谢综合征、II 型糖尿病和心血管疾病 (CVD) 相关。更好地了解控制高密度脂蛋白和甘油三酯循环水平的调节机制可能会产生对抗心脏代谢疾病的新治疗途径。我们最近令人惊讶地发现，编码胆固醇/脂质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 microRNA（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 HDL 合成的关键抑制剂，可提高细胞内胆固醇水平，注射针对 miR-33a 的反义寡核苷酸可显着提高西式饮食小鼠的 HDL 水平。我们在此提出测试以下假设：miR-33a/b 代表哺乳动物胆固醇/脂质代谢多个方面的中央调节因子，与 SREBP 宿主基因密切合作。小鼠和非人类灵长类动物的体外细胞培养和体内研究都将为 miR-33a/b 在靶向引导脂质和能量稳态的整个途径中的作用以及 miR-33a/b 是否合适提供关键的机制见解用于提高代谢综合征患者循环 HDL 和降低血浆甘油三酯的治疗目标。