Carboxylesterase 1 in Alcoholic Liver Disease

项目摘要 项目概述：酒精性肝病（ALD）是全球晚期肝病的主要原因。ALD 包括一系列肝脏疾病，从简单的脂肪变性到更严重的肝损伤， 包括酒精性脂肪性肝炎、肝硬化和肝细胞癌。为了降低ALD的发病率， 戒酒对于预防ALD的发展至关重要。从治疗 然而，在过去的40年里，ALD的治疗进展甚微。 羧酸酯酶1（CES 1）是一种药物代谢酶，在肝脏中高度表达， 肠、巨噬细胞、心脏、胰腺、肾脏和脂肪组织中的程度。CES 1同时具有 甘油三酯（TG）和胆固醇酯水解酶活性。我们之前已经证明CES 1抑制了 通过调节TG水解、FAO和脂肪生成来实现肝脏TG蓄积。肝CES 1功能获得 还显示出改善糖尿病或高脂肪饮食喂养的小鼠的胰岛素敏感性。我们的初步数据显示 Ces 1-/-小鼠表现出加重的酒精诱导的肝损伤和炎症，同时过度表达 CES 1抑制炎症和乙醇诱导的TG积累。根据这些观察，我们 推测肝CES 1在ALD的发病机制中起保护作用。为了验证这个假设， 我们将使用肝脏特异性Ces 1基因敲除或转基因小鼠来研究肝脏Ces 1在ALD中的作用， 以及潜在的机制。此外，我们还将研究乙醇对CES 1的调控。 这些研究的完成将有助于阐明肝脏CES 1在ALD发病机制中的作用 并且可能导致将CES 1鉴定为治疗ALD的有吸引力的靶标。

Project Summary Project Summary: Alcoholic liver disease (ALD) is a major cause of advanced liver disease worldwide. ALD consists of a spectrum of liver disorders, ranging from simple steatosis to more severe forms of liver injury, including alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. To reduce the incidence of ALD, abstinence from alcohol abuse is critical for prevention of the development of ALD. From the therapeutic standpoint, however, little progress has been made towards the treatment of ALD over the past 40 years. Carboxylesterase 1 (CES1) is a drug-metabolizing enzyme that is highly expressed in the liver and to a lesser extent in intestine, macrophages, heart, pancreas, kidney and adipose tissue. CES1 possesses both triglyceride (TG) and cholesterol ester hydrolase activity. We have previously shown that CES1 inhibits hepatic TG accumulation by regulating TG hydrolysis, FAO and lipogenesis. Gain of hepatic CES1 function is also shown to improve insulin sensitivity in diabetic or high fat diet-fed mice. Our preliminary data show that Ces1 -/- mice display aggravated alcohol-induced liver injury and inflammation while over-expression of CES1 inhibits inflammation and ethanol-induced TG accumulation. Based on these observations, we hypothesize that hepatic CES1 plays a protective role in the pathogenesis of ALD. To test this hypothesis, we will use liver-specific Ces1 knockout or transgenic mice to investigate the role of hepatic CES1 in ALD as well as the underlying mechanism. In addition, we will also investigate the regulation of CES1 by ethanol. Completion of the proposed studies will help elucidate the role of hepatic CES1 in the pathogenesis of ALD and may lead to identification of CES1 as an attractive target for treatment of ALD.