Hepatic Wnt/LRP6 Regulation of Plasma Lipids

肝脏 Wnt/LRP6 对血浆脂质的调节

基本信息

批准号：
9174908
负责人：
Arya Mani
金额：
$ 21.84万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-19 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174908
关键词：
Address Animal Model Apolipoproteins B Atherosclerosis Cardiovascular Diseases Cells Cholesterol Clinical Research Combined Modality Therapy Coronary Arteriosclerosis Coronary artery Crossbreeding Development Diabetes Mellitus Diet Disease Disease Pathway Drug Targeting Exhibits FRAP1 gene Familial Combined Hyperlipidemia Fatty Liver Functional disorder General Population Genes Genetic Predisposition to Disease Genetic study Hepatic Hepatocyte Heterozygote Homeostasis Homozygote Human Hyperlipidemia IGF1 gene IGF1R gene Impairment Individual Insulin Investigation Knock-out Knockout Mice LDL Cholesterol Lipoproteins Link Lipids Lipoproteins Liver Liver diseases Low-Density Lipoproteins Mediator of activation protein Metabolic syndrome Modeling Molecular Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Online Mendelian Inheritance In Man Pathway interactions Phenotype Phosphorylation Plasma Point Mutation Proteins Proto-Oncogene Proteins c-akt Regulation Risk Risk Factors Role Science TCF7L2 gene Therapeutic Agents Triglycerides Variant Very low density lipoprotein WNT Signaling Pathway Wnt proteins beta catenin biological systems early onset genetic variant human disease insulin signaling lipid biosynthesis lipid disorder loss of function mutation low density lipoprotein triglyceride metabolic phenotype mouse model new therapeutic target novel novel therapeutics overexpression prevent public health relevance therapeutic development transcription factor

项目摘要

DESCRIPTION (provided by applicant): The genetic etiology and the molecular mechanisms of combined hyperlipidemia (CHL), the most common lipid disorder of the general population is not understood. Accordingly, no single therapeutic agent is available that completely normalizes both plasma LDL and TG, and or prevent cardiovascular disease. We have identified rare loss of function mutations in Wnt coreceptor LRP6 that underlie early atherosclerosis, and metabolic phenotypes including CHL. Since our initial discovery altered plasma levels and or functions of Wnt proteins and LRP6 antagonists have been associated with risk of hyperlipidemia and early onset CAD in the general population. In addition, common variants in Wnt transcription factor TCF7L2 have been associated with familial CHL. These findings have implicated Wnt signaling in hyperlipidemia and early onset atherosclerosis. To investigate disease mechanisms, mice with the human LRP6R611C (LRP6mut/mut) point mutation were generated. LRP6mut/mut mice exhibit significantly elevated plasma triglycerides (TG) and LDL cholesterols on high cholesterol diet, which dramatically increases after they are crossbred onto LDLR/ mice. Further studies in these mice revealed enhanced expression of liver IGF1/IGF1R associated with augmented activities of AKT/mTOR pathways, leading to increased SREBP1 and 2 activation, lipid synthesis and ApoB secretion. Strikingly, these changes normalized and hyperlipidemia was rescued by systemic Wn3a administration. We have devised several mouse models and propose to study the role of canonical Wnt/ß-catenin/ TCF7L2, and their potential downstream pathways IGF1 and mTORC2 in regulation of lipid synthesis and ApoB secretion. These studies hold great promise for identifying novel pathways and potential targets for development of therapeutics against combined hyperlipidemia.

描述（由申请人证明）：可获得一般人群的遗传病因和分子机制（CHL）ER，可获得血浆LDL和 /或预防心血管疾病的血浆LDL。早期的LRP6和包括CHL在内的代谢表型改变了血浆水平或与Hyperial Chl中的高脂和早期发作CAD相关的n功能。动脉粥样硬化。我们已经使用了SEVIONS。识别新的途径和潜在靶标，用于开发针对混合高脂血症的疗法的潜在靶标。