Identification of Novel Genes/Pathways That Regulate Lipid and Glucose Metabolism

描述（由申请人提供）：非酒精性脂肪肝（NAFLD）是指广泛的肝脏疾病，从肝脂肪变性到非酒精性脂肪性肝炎、纤维化和肝硬化。NAFLD通常与肥胖、胰岛素抵抗、2型糖尿病和血脂异常有关。Farnesoid X受体（FXR）是一种核激素受体，在维持胆汁酸、脂质和葡萄糖的稳态中起重要作用。我们的长期目标是确定调节脂质和碳水化合物代谢的新基因/途径，并阐明潜在的机制。FXR的激活已被证明可以降低肝脏和血浆甘油三酯水平。虽然FXR调节血浆甘油三酯水平的机制已经被很好地理解，但激活FXR降低肝脏甘油三酯水平的机制仍有待阐明。最近的数据表明，FXR是治疗NAFLD的治疗靶点。因此，阐明激活FXR降低肝脏甘油三酯水平的机制既重要又必要。羧酸酯酶1 （CES1）主要在肝脏高度表达。我们的初步数据表明，i)高血糖水平诱导肝脏CES1表达，ii)肝脏CES1过表达显著降低肝脏甘油三酯水平，降低血浆葡萄糖水平，提高葡萄糖耐量，iii)肝脏CES1缺失显著增加肝脏甘油三酯水平，iv) FXR激活高度诱导肝脏CES1表达。这些初步数据非常令人兴奋，因为它们首次提供了体内证据，证明肝脏CES1可能在调节肝脏甘油三酯和葡萄糖稳态中发挥重要作用。在本研究中，我们将进一步确定肝脏CES1在控制葡萄糖和肝脏甘油三酯稳态以及FXR信号传导中的作用。我们将利用转基因小鼠，结合生物化学、分子和细胞以及药理学方法来完成拟议的研究。完成本提案的具体目标将为FXR调节肝脏甘油三酯水平的机制提供重要见解，并可能确定一种调节血浆葡萄糖水平的新型ces1 -葡萄糖- ces1途径。最后，这些研究的完成可能会导致肝脏CES1作为治疗NAFLD的治疗靶点。

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver (NAFLD) refers to a wide spectrum of liver disorders ranging from hepatic steatosis to nonalcoholic steatohepatitis, fibrosis and cirrhosis. NAFLD is often associated with obesity, insulin resistance, type 2 diabetes and dyslipidemia. Farnesoid X receptor (FXR) is a nuclear hormone receptor and plays an important role in maintaining bile acid, lipid and glucose homeostasis. Our long-term goal is to identify novel genes/pathways that regulate lipid and carbohydrate metabolism and to elucidate the underlying mechanism(s). Activation of FXR has been shown to lower both hepatic and plasma triglyceride levels. While the mechanism by which FXR regulates plasma triglyceride levels is well understood, the mechanism whereby activation of FXR lowers hepatic triglyceride levels remains to be elucidated. Recent data have suggested that FXR is a therapeutic target for treatment of NAFLD. Thus, elucidation of the mechanism by which activation of FXR lowers hepatic triglyceride levels is both important and necessary. Carboxylesterase 1 (CES1) is highly and principally expressed in the liver. Our preliminary data have shown that i) high blood glucose levels induce hepatic CES1 expression, ii) over-expression of hepatic CES1 markedly reduces hepatic triglyceride levels, lowers plasma glucose levels, and improves glucose tolerance, iii) loss of hepatic CES1 significantly increases hepatic triglyceride levels, and iv) activation of FXR highly induces hepatic CES1 expression. These preliminary data are quite exciting, as they provide the first in vivo evidence that hepatic CES1 may play an important role in regulating hepatic triglyceride and glucose homeostasis. In this proposal, we will further determine the role of hepatic CES1 in controlling glucose and hepatic triglyceride homeostasis and in FXR signaling. We will utilize genetically modified mice, in combination with biochemical, molecular and cellular, and pharmacological approaches to finish the proposed studies. Accomplishing the specific aims in this proposal will provide important insights into the mechanism by which FXR regulates hepatic triglyceride levels, and may identify a novel CES1-glucose-Ces1 pathway that regulates plasma glucose levels. Finally, completion of the proposed studies may lead to identification of hepatic CES1 as a therapeutic target for treatment of NAFLD. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in humans. Completion of the proposed studies will help determine how FXR regulates hepatic triglyceride metabolism and whether hepatic carboxylesterase 1 is a potential target for treatment of NAFLD. Thus, the studies proposed in this application are highly relevant to fatty liver disease and human health.