FXR ALTERS HEPATIC LIPID METABOLISM & DECREASES FATTY LIVER DEVELOPMENT

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该提议的中心假设是，法尼醇-X-受体（FXR）与核受体网络协作，通过调节脂肪酸和甘油三酯的摄取、细胞内转运、脂肪生成、氧化和分泌在肝脏中的脂肪酸和甘油三酯代谢中起关键作用。脂肪酸是各种细胞过程的关键，并以甘油三酯的形式储存。哺乳动物肝脏在调节脂肪酸和甘油三酯代谢中起着至关重要的作用。肝脏中脂质的异常积累会导致肝损伤，这种情况称为脂肪肝或肝脂肪变性。最近的证据表明，FXR，配体激活的转录因子和核受体的胆汁酸，是中央在调节脂质稳态。小鼠FXR基因缺失导致脂肪肝形成。然而，FXR调节肝脏脂质代谢的机制尚不清楚。该研究的目的是确定FXR调节肝脏脂质代谢的机制。为实现这一目标，提出了以下三个具体目标。目的1将确定FXR和过氧化物酶体增殖物激活受体（PPAR）γ之间的相互作用，在调节脂肪酸摄取，细胞内转运，并转化为甘油三酯。 目的2是确定FXR通过与PPARgamma相互作用调节脂肪酸氧化的机制。目的3探讨FXR在调节肝脏甘油三酯分泌中的作用。本研究结果将阐明FXR在调节肝脏脂质代谢、脂肪肝形成中的作用，并为预防和治疗脂质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.