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 farnesoid-X-receptor (FXR), in concert 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/or secretion. Fatty acids are crucial for a variety of cellular processes and are 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 ligandactivated transcription factor and member of the nuclear receptor superfamily, is crucial 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. I have made a hepatocyte-specific FXR-null mouse line, which will serve as a novel tool to study specifically the role of FXR in liver. The goal of this study is to identify the mechanisms by which FXR regulates hepatic lipid metabolism using hepatocytespecific FXR-null mice with three specific aims.
Aim 1 will determine the role of FXR in suppressing the peroxisome-proliferators-activated receptor gamma (PPARgamma)-regulated pathway of hepatic fatty acid uptake, intracellular transport, and conversion to triglycerides.
Aim 2 is to determine the mechanism by which FXR regulates fatty acid oxidation in liver by activation of PPARalpah.
Aim 3 will investigate the specific role of FXR in regulating triglyceride secretion from liver. Results from this work will elucidate the mechanisms by which FXR regulates hepatic lipid metabolism and fatty liver formation, as well as provide potential therapeutic targets for preventing and treating abnormalities in lipid metabolism.
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