FXR ALTERS HEPATIC LIPID METABOLISM & DECREASES FATTY LIVER DEVELOPMENT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这一建议的中心假设是，法尼类X受体(FXR)与核受体网络合作，通过调节脂肪酸和甘油三酯的摄取、细胞内运输、脂肪生成、氧化和分泌，在肝脏的脂肪酸和甘油三酯代谢中发挥关键作用。脂肪酸是各种细胞过程的关键，以甘油三酯的形式储存。哺乳动物的肝脏在调节脂肪酸和甘油三酯代谢方面起着至关重要的作用。肝脏中脂质的异常积聚会导致肝脏损伤，这种情况被称为脂肪肝或肝脏脂肪变性。最近的证据表明，FXR是一种配体激活的转录因子和胆汁酸的核受体，在调节脂质平衡方面发挥着核心作用。小鼠中FXR基因的缺失会导致脂肪肝的形成。然而，FXR调节肝脏脂质代谢的机制尚不清楚。本研究的目的是确定FXR调节肝脂代谢的机制。为实现这一目标，提出了以下三个具体目标。目的1确定FXR和PPAR在调节脂肪酸摄取、细胞内转运和转化为甘油三酯方面的相互作用。目的2是确定FXR通过与PPAR-γ相互作用来调节脂肪酸氧化的机制。目的3研究FXR在调节肝脏甘油三酯分泌中的特殊作用。本工作的结果将阐明FXR在调节肝脏脂代谢、脂肪肝形成中的作用，并为预防和治疗脂代谢异常提供潜在的治疗靶点。

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.