Carboxylesterase 1 in Alcoholic Liver Disease

酒精性肝病中的羧酸酯酶 1

基本信息

批准号：
9196434
负责人：
Yanqiao Zhang
金额：
$ 21.79万
依托单位：
NORTHEAST OHIO MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-10 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9196434
关键词：
4 hydroxynonenal 5&apos -AMP-activated protein kinase ADD-1 protein Acetaldehyde Acetyl-CoA Carboxylase Adipose tissue Alcohol abuse Alcohol consumption Alcoholic Fatty Liver Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Bile Acids Cells Cirrhosis Data Deacetylase Development Energy Metabolism Enzymes Ethanol Ethanol Metabolism Exhibits Exposure to Fatty Liver Genetic Transcription Glucose Health Heart Hepatic High Fat Diet Human Hydrolysis Incidence Inflammation Intestines Investigation Kidney Knockout Mice Lead Lipids Lipolysis Lipopolysaccharides Liver Liver Cirrhosis Liver diseases Malondialdehyde Microtubules Mitochondria Mus NADH Nonesterified Fatty Acids Nuclear Hormone Receptors PPAR alpha Palmitic Acids Pancreas Pathogenesis Patients Pharmaceutical Preparations Play Prevention Primary carcinoma of the liver cells Reactive Oxygen Species Regulation Role SRE-1 binding protein Steatohepatitis Testing Therapeutic Transgenic Mice Triglycerides Very low density lipoprotein Wild Type Mouse Xenobiotics alcohol abstinence base carboxylesterase diabetic drug metabolism feeding glucose metabolism hepatic nuclear factor 1 hepatocyte nuclear factor improved insight insulin sensitivity lipid biosynthesis lipid metabolism liver inflammation liver injury macrophage metabolome novel overexpression problem drinker response sterol esterase therapeutic target transcriptome treatment strategy uptake western diet

项目摘要

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.

项目概要项目摘要：酒精性肝病（ALD）是全世界晚期肝病的主要原因。酒精性肝病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 的发生率，戒酒对于预防 ALD 的发展至关重要。从治疗上然而，从角度来看，过去 40 年来 ALD 的治疗几乎没有取得任何进展。羧酸酯酶 1 (CES1) 是一种药物代谢酶，在肝脏中高度表达，但表达较少范围在肠道、巨噬细胞、心脏、胰腺、肾脏和脂肪组织中。 CES1 两者兼具甘油三酯（TG）和胆固醇酯水解酶活性。我们之前已经证明 CES1 抑制通过调节 TG 水解、FAO 和脂肪生成来促进肝脏 TG 积累。肝 CES1 功能的获得还被证明可以提高糖尿病或高脂肪饮食喂养小鼠的胰岛素敏感性。我们的初步数据显示 Ces1 -/- 小鼠表现出严重的酒精诱导的肝损伤和炎症，同时过度表达 CES1 抑制炎症和乙醇诱导的 TG 积累。根据这些观察，我们假设肝脏CES1在ALD的发病机制中发挥保护作用。为了检验这个假设，我们将使用肝脏特异性 Ces1 敲除或转基因小鼠来研究肝脏 CES1 在 ALD 中的作用以及底层机制。此外，我们还将研究乙醇对CES1的调控。完成拟议的研究将有助于阐明肝脏 CES1 在 ALD 发病机制中的作用并可能导致将 CES1 确定为治疗 ALD 的有吸引力的靶点。