Mechanisms of Hippo signaling in Alcoholic liver disease

Hippo 信号在酒精性肝病中的机制

• 批准号: 9296288
• 负责人: Yingzi Yang
• 金额: $ 24.37万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296288
• 关键词: Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic liver damage; Alcohols; Attenuated; Cell Death; Chronic; Cirrhosis; Data; Disease; Down-Regulation; Drosophila genus; Ethanol; Foundations; Genetic; Goals; Hepatocyte; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Innate Immune Response; Investigation; Knowledge; Lead; Liver; Liver Failure; Liver Regeneration; Mammals; Mediating; Modeling; Molecular; Morbidity - disease rate; Natural regeneration; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Play; Primary carcinoma of the liver cells; Production; Proteins; Regulation; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Solid; Steatohepatitis; TLR4 gene; Therapeutic; Tissues; adaptive immune response; alcohol abuse therapy; alcohol effect; chronic alcohol ingestion; cytokine; cytotoxic; driving force; feeding; in vivo; liver cell proliferation; liver inflammation; liver injury; macrophage; mortality; mouse model; mutant; problem drinker; restoration; transcription factor

Alcoholic liver disease (ALD), a major cause of morbidity and mortality worldwide, includes a broad spectrum of disorders, ranging from simple steatosis to severe forms of liver injury such as steatohepatitis, alcoholic hepatitis, cirrhosis, liver failure and hepatocellular carcinoma. Aside from the direct cytotoxic and the oxidative- stress–mediated effects that alcohol and its metabolites exert on hepatocytes, alcohol ingestion also activates both the innate and adaptive immune responses in the liver, and dysregulates several important signaling pathways in the liver, thereby contributing to the pathogenesis of ALD. Recent studies suggest that impaired liver regeneration and inflammation are two important mechanisms contributing to liver failure in patients with alcoholic hepatitis. However, the underlying mechanisms remain unclear. The Hippo (Hpo) signaling pathway has recently emerged as a critical one regulating hepatocyte proliferation, survival as well as inflammation. Central to the Hpo pathway is the control of Yap/Taz transcription factors by a kinase cascade starting from the Hpo kinase, which are Mst1 and Mst2 in mammals. As hepatocyte injury is a major driving force for ALD pathogenesis, the goal of this explorative R21 proposal is to determine whether alcohol attenuates liver regeneration and induces liver inflammation by dysregulating the Hpo signaling pathway in hepatocytes. Despite the critical functions of Hpo signaling in restricting hepatocyte proliferation and survival we and others have identified, the precise functions and molecular mechanisms whereby the Hpo signaling pathway participates in alcohol-induced liver injury, inflammation and regeneration are mostly unknown. Hence, there are many unanswered fundamental questions regarding Hpo signaling in ALD. The knowledge gained from the proposed studies will establish a solid new foundation for further mechanistic investigation of Hpo signaling in ALD and provide new targets and strategies to protect liver from alcohol induced injury. Our unpublished preliminary data show that in a short-term chronic-binge ALD (E1d-1B) model, Mst1, Mst2 and Yap protein levels were reduced. We have also found that, infiltrated macrophage numbers and expression of pro- inflammatory cytokines are increased in the hepatocyte-specific Mst1 and Mst2 double mutant (DKO) liver. We hypothesize that reduction in Yap expression leads to increased hepatocyte cell death and impaired hepatocyte regeneration; while Mst1 and Mst2 down-regulation in hepatocytes of the alcoholic liver contributes to chronic pro-injury liver inflammation. In Specific Aim 1, we will define the effects of alcohol consumption on the Hpo signaling pathway in hepatocytes. In Specific Aim 2, we will determine whether alcohol feeding inhibits liver regeneration by reducing Yap in hepatocytes. In Specific Aim 3, we will determine whether alcohol feeding causes liver inflammation by reducing Mst1 and Mst2 in hepatocytes.

酒精性肝病（ALD）是世界范围内发病率和死亡率的主要原因之一，其发病范围很广