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Roles of ANGPTL3 and ANGPTL8 in Lipid and Energy Metabolism

ANGPTL3 和 ANGPTL8 在脂质和能量代谢中的作用

基本信息

批准号：
10183293
负责人：
Helen Haskell Hobbs
金额：
$ 64.92万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183293
关键词：
ANGPTL3 gene Address Adipose tissue Angiopoietins Antibodies Basal metabolic rate Body Temperature Cardiovascular Diseases Cardiovascular system Cholesterol Cholesterol Homeostasis Clinical Complement Complex Coronary heart disease DNA Sequence Development Disease Energy Metabolism Enzyme-Linked Immunosorbent Assay Fatty acid glycerol esters Functional disorder Funding Gene Family Generations Genes Genetic Genetic Determinism Goals Grant Heart Human Human Genetics Impairment Individual Knockout Mice LDL Cholesterol Lipoproteins Laboratories Link Lipids Lipoproteins Literature Liver Logic Metabolic Metabolic Diseases Metabolic Pathway Metabolism Molecular Monoclonal Antibodies Mus Mutation Names Outcome Peripheral Pharmaceutical Preparations Phenotype Physiology Plasma Play Population Population Study Process Proteins Reagent Research Project Grants Risk Factors Role Testing Therapeutic Therapeutic Intervention Tissues Triglyceride Metabolism Triglycerides Variant genetic approach inhibitor/antagonist insight insulin sensitivity lipid metabolism loss of function loss of function mutation member mouse model multi-ethnic new therapeutic target paralogous gene progenitor reverse genetics therapeutic target trafficking trait virtual

项目摘要

Plasma levels of lipoproteins are major risk factors for coronary heart disease (CHD). Our laboratory has used human genetics to elucidate the physiology and pathophysiology of circulating lipoproteins, and identify new targets for therapeutic intervention. Here we focus on the angiopoietin-like proteins 3 and 8 (ANGPTL3 and ANGPTL8), which exert powerful effects on lipoprotein metabolism. Humans lacking ANGPTL3 have striking panhypolipidemia, with marked reductions in plasma levels of LDL-cholesterol and triglycerides (TG). In the last funding period we showed that ANGPTL8 (A8) is a paralog of ANGPTL3 (A3)) that acts together with its progenitor to direct trafficking of circulating TG to peripheral tissues. Deficiency of ANGPTL8 reduces plasma levels of TG in both humans and mice. More recently, our group demonstrated that A3 and A8 both play a critical role in energy metabolism. Mice lacking the two genes are hypermetabolic, with increased body temperatures, increased VO2 and impaired fat accumulation. In contrast to the extensive literature on the effect of genetic differences in A3 and A8 on circulating lipoproteins, virtually nothing is known about the roles of these two proteins in energy metabolism. In this proposal, we will address 3 questions: 1) What are the roles of A3 and A8 in lipid and energy metabolism? 2) What is the potential therapeutic utility of inactivating A3 and/or A8? 3) How does variation in plasma A3 or A8 levels impact on other metabolic pathways humans? In Aim 1, genetically-modified mice will be used to investigate the actions of A3 and A8 on TG trafficking and energy metabolism. Unlike A3, A8 is expressed in adipose tissue as well as liver; therefore, we will use tissue-specific A8 KO mice to determine the function of A8 in the two tissues. We will then investigate the metabolic and molecular basis for the remarkable and unexpected increases in body temperature and basal metabolic rate observed in mice lacking both A3 and A8. In Aim 2 we will use monoclonal antibodies (mAbs) to assess the therapeutic potential of singly and jointly inactivating circulating A3 and A8. In Aim 3 we will use newly developed anti-A8 antibodies (Ab) to establish a sensitive and specific ELISA to quantify A8 in plasma. For these studies we will take advantage of a well-characterized population-based study that we established in Dallas, the Dallas Heart Study, to determine how plasma levels of A8 are related to metabolic and cardiovascular disease in humans. The reagents and expertise required for the studies outlined in this grant are already established in our laboratory. Successful completion of these studies will elucidate an important metabolic pathway and could provide the impetus for development of a new generation of lipid-lowering drugs that reduce plasma lipid levels and promote energy utilization. C/PPG 2015 – RP4 – 30-line Summary

血浆脂蛋白水平是冠心病（CHD）的主要危险因素。我们的实验室有