Molecular Biology of Bile Acid Synthesis

描述（由申请人提供）：胆汁酸信号传导在控制肝脏代谢和炎症中起关键作用。有毒胆汁酸的积累导致肝脏炎症，并有助于慢性非酒精性脂肪性肝病（NAFLD），糖尿病和肥胖症的发病机制。胆汁酸合成速率受第一限速酶胆固醇7α-羟化酶（CYP 7A 1）调节，而胆汁酸合成中胆汁酸组成受甾醇12α-羟化酶（CYP 8B 1）调节。胆汁酸激活核受体FXR和G蛋白偶联受体TGR 5以调节脂质、葡萄糖和能量代谢。已经提出FXR在胆汁酸合成的胆汁酸反馈抑制中起关键作用。胆汁酸的抗炎作用最近已被认识到。然而，胆汁酸调节肝脏代谢稳态和炎症的潜在分子机制尚不清楚。2型糖尿病患者血清12α-羟化胆汁酸水平升高，与胰岛素抵抗和血脂异常相关。设计了三个具体目标来检验FXR和TGR 5信号传导调节胆汁酸合成和组成的假设，这影响肝脏炎症、胰岛素抵抗、NAFLD和肥胖。具体目标1是研究FXR和TGR 5信号在胆汁酸代谢中的作用机制。FXR-/-、TGR 5-/-和FXR/TGR 5双敲除（DK）小鼠将用于检验FXR/TGR 5/CYP 8B 1途径可能在胆汁酸合成和脂质代谢调节中发挥作用的假设。具体目标2是研究TGR 5和FXR信号传导在肝细胞中的抗炎作用。FXR和TGR 5信号传导的激活可影响巨噬细胞极化以减少肝脏炎症。TGR 5-/-、FXR-/-和FXR/TGR 5 DK小鼠将用于研究FXR和TGR 5的抗炎作用机制。具体目标3是研究昼夜节律和禁食/限制进食对NAFLD、胰岛素抵抗和肥胖中胆汁酸合成的营养调节。禁食限饲和高脂饮食影响胆汁酸合成和能量代谢的昼夜节律。本实验旨在研究CYP 8B 1在血脂异常、胰岛素抵抗和NAFLD中的作用。本研究对于阐明胆汁酸合成和脂质稳态调节的分子机制以及肝脏相关代谢疾病的发病机制具有重要意义。这项研究的结果将有可能开发药物治疗，以改善胰岛素敏感性，肝脏炎症，肝脂肪变性，糖尿病和肥胖症。

DESCRIPTION (provided by applicant): Bile acid signaling plays a critical role in control of liver metabolism and inflammation. Accumulation of toxic bile acids causes liver inflammation and contributes to pathogenesis of chronic non-alcoholic fatty liver disease (NAFLD), diabetes and obesity. The rate of bile acid synthesis is regulated by the first and rate- limiting enzyme, cholesterol 7α-hydroxylase (CYP7A1), whereas bile acid composition is regulated by sterol 12α-hydroxylase (CYP8B1) in cholic acid synthesis. Bile acids activate a nuclear receptor FXR and a G protein coupled receptor TGR5 to regulate lipid, glucose and energy metabolism. It has been proposed that FXR plays a key role in bile acid feedback inhibition of bile acid synthesis. The anti-inflammatory action of bile acids has been recognized recently. However, the underlying molecular mechanisms of bile acid regulation of hepatic metabolic homeostasis and inflammation are not understood. Type 2 diabetes patients have higher serum 12α-hydroxylated bile acids, which is correlated to insulin resistance and dyslipidemia. Three specific aims are designed to test the hypothesis that FXR and TGR5 signaling regulate bile acid synthesis and composition, which affect hepatic inflammation, insulin resistance, NAFLD and obesity. Specific aim 1 is to study the mechanisms of FXR and TGR5 signaling in bile acid metabolism. FXR-/-, TGR5-/- and FXR/TGR5 double knockout (DK) mice will be used to test the hypothesis that the FXR/TGR5/CYP8B1 pathway may play a role in regulation of bile acid synthesis and lipid metabolism. Specific aim 2 is to study TGR5 and FXR signaling in anti-inflammation in hepatocytes. Activation of FXR and TGR5 signaling may affect macrophage polarization to reduce hepatic inflammation. TGR5-/-, FXR-/- and FXR/TGR5 DK mice will be used to study the mechanisms of anti-inflammatory action of FXR and TGR5. Specific aim 3 is to study nutrient regulation of the diurnal rhythm and fasting/restricted feeding on bile acid synthesis in NAFLD, insulin resistance and obesity. Fasting and restricted feeding and high fat diet affect the circadian rhythm of bile acid synthesis and energy metabolism. Experiments are designed to study the role of CYP8B1 in dyslipidemia, insulin resistance and NAFLD. This study is highly significant in elucidating the molecular mechanisms of regulation of bile acid synthesis and lipid homeostasis, and pathogenesis of liver-related metabolic diseases. Results from this study will have potential for developing drug therapies to improve insulin sensitivity, liver inflammation, hepatic steatosis, diabetes and obesity.