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The role of FSP27b on dietary lipid absorption, lipoprotein secretion, and oxidative metabolism

FSP27b 对膳食脂质吸收、脂蛋白分泌和氧化代谢的作用

基本信息

批准号：
10552559
负责人：
Angel Baldan
金额：
$ 34.09万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10552559
关键词：
Acceleration Address Adipocytes Agonist Amendment Antisense Oligonucleotides Area Attention Basic Science Biochemical Bioenergetics Biogenesis Biological Assay Biology Blood Brown Fat Cardiac Myocytes Cardiometabolic Disease Cardiovascular Diseases Catabolism Cell Respiration Cells Chylomicrons Clinical Clinical Sciences Cultured Cells Data Diet Dietary Fats Disease Drug or chemical Tissue Distribution Dyslipidemias Energy Metabolism Equilibrium Familial partial lipodystrophy Fasting Fatty Acids Future Genes Genetic Genetic Polymorphism Goals Hepatic Hepatocyte High Prevalence Homeostasis Human Hyperlipidemia Incidence Insulin Resistance Intervention Intestines Knowledge Label Laboratories Lead Lipids Lipoproteins Liver LoxP-flanked allele Mediating Medical Metabolic Metabolism Mitochondria Molecular Mus Muscle Muscle Fibers Norepinephrine Nutritional Obesity Organ Pathologic Pathway interactions Patients Pattern Peripheral Peroxisome Proliferator-Activated Receptors Physiological Physiology Plasma Population Protein Isoforms Proteins Public Health Publishing Reporting Research Rest Risk Role Signal Transduction Techniques Testing Therapeutic Therapeutic Intervention Thermogenesis Tissue Transplantation Tissues Transgenic Organisms Transplantation Triglyceride Metabolism Triglycerides Very low density lipoprotein Work absorption base cardiovascular risk factor circadian diet-induced obesity experimental study fatty liver disease frontier gain of function human disease improved in vivo in vivo monitoring innovation intestinal epithelium knock-down lipid metabolism loss of function loss of function mutation mouse model neglect new therapeutic target novel obesity treatment overexpression oxidation pharmacologic response success

项目摘要

SUMMARY The proposed work will define the role of the lipid droplet-associated protein CIDEC (also known as FSP27) on the metabolic fate of lipids in liver and intestine, circulating lipoproteins, and oxidative lipid metabolism in muscle and brown adipose tissue (BAT). Dysregulation of lipid metabolism is the basis of some of the most common medical disorders in Western populations, such as cardiovascular disease, hyperlipidemia, fatty liver diseases, obesity, and insulin resistance. The long-term goal in our laboratory is to elucidate molecular and cellular mechanisms governing whole-body lipid homeostasis, both under physiological and pathological conditions. CIDEC/FSP27 encodes 2 isoforms, a and b, with strict tissue distribution. Here we will exploit Fsp27bKO mice to reveal the role of FSP27b (the sole FSP27 expressed in liver and intestine, and the major isoform in BAT) on the partitioning of lipids for storage/oxidation/secretion. We will test the new ideas that FSP27b is a critical regulator of hepatic APOB lipidation and secretion, dietary lipid absorption and postprandial lipemia, and fatty acid utilization in peripheral tissues. The proposed studies will be transformative for our understanding of: i) mechanisms governing the biogenesis and secretion of pro-atherogenic lipoproteins; ii) lipid biology in major oxidative tissues; and iii) metabolic cross-talk between liver and other tissues, an area that has been largely neglected in the past. To achieve the goal of defining the role of FSP27b on lipid metabolism, we plan three specific aims. Aim 1 will test the hypothesis that FSP27b promotes the lipidation and secretion of APOB-containing lipoproteins in liver and intestine. Aim 2 will test the hypothesis that hepatic FSP27b limits the availability of PPAR agonists for peripheral tissues. Aim 3 will test the hypothesis that FSP27b reduces energy expenditure in brown adipose tissue. Importantly, some of the proposed research will correct the published scientific record on FSP27, which is based on a flawed “Fsp27-floxed” mice. The translational relevance of our studies is highlighted by reports showing that polymorphisms in FSP27 are associated with elevated fasting triglyceridemia in humans, and that loss-of- function mutations result in familial partial lipodystrophy, type 5 (FPLD5). Overall, success of the proposed studies will fill a large gap of knowledge in whole-body lipid (patho)physiology, by defining molecular mechanisms of lipid droplet-mediated control of triglyceride metabolism in liver, intestine, muscle, and brown adipose tissue, with particular attention to multi-organ metabolic cross-talk via circulating lipids. These studies may also establish FSP27 as a valid pharmacological target to manage fatty liver diseases, diet-induced obesity, dyslipidemias, and cardiovascular risk in patients.

总结