FXR ALTERS HEPATIC LIPID METABOLISM & DECREASES FATTY LIVER DEVELOPMENT

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The central hypothesis of this proposal is that the farnesoid-X-receptor (FXR), in collaboration with a network of nuclear receptors, plays a pivotal role in fatty acid and triglyceride metabolism in liver by regulating their uptake, intracellular transport, lipogenesis, oxidation, and secretion. Fatty acids are pivotal for a variety of cellular processes and stored in the form of triglycerides. The mammalian liver plays a crucial role in regulating fatty acid and triglyceride metabolism. Abnormal accumulation of lipid in liver causes liver damage, a condition known as fatty liver or hepatic steatosis. Recent evidence showed that FXR, a ligand-activated transcriptional factor and nuclear receptor for bile acids, is central in regulating lipid homeostasis. Deletion of the FXR gene in mice leads to fatty liver formation. However, the mechanisms by which FXR regulates lipid metabolism in liver remain unclear. The goal of the study is to identify the mechanisms by which FXR regulates hepatic lipid metabolism. Three specific aims listed below are proposed to reach this goal. Aim 1 will determine the interaction between FXR and peroxisome-proliferator-activated receptor (PPAR) gamma in regulating fatty acid uptake, intracellular transport, and conversion to triglycerides. Aim 2 is to determine the mechanism by which FXR regulates fatty acid oxidation by interaction with PPARgamma. Aim 3 will investigate the specific role of FXR in regulating triglyceride secretion from liver. Results from this work will elucidate the role of FXR in regulating hepatic lipid metabolism, fatty liver formation, and provide potential therapeutic targets in preventing and treating abnormalities in lipid metabolism.