Mechanisms of Hippo signaling in Alcoholic liver disease

酒精性肝病(ALD)是世界范围内发病率和死亡率的主要原因，包括广泛的 疾病，从简单的脂肪变性到严重的肝脏损伤，如脂肪性肝炎、酒精性 肝炎、肝硬变、肝衰竭和肝细胞癌。除了直接的细胞毒性和氧化性- 酒精及其代谢产物对肝细胞的应激调节作用，酒精摄入也会激活 肝脏中的先天和获得性免疫反应，并调节几个重要的信号 肝细胞外信号转导通路，从而参与ALD的发病。最近的研究表明，受损的人 肝再生和炎症是导致慢性肝炎患者肝功能衰竭的两个重要机制 酒精性肝炎。然而，潜在的机制仍不清楚。河马(Hpo)信号通路 最近成为调节肝细胞增殖、存活和炎症的关键因子。 HPO途径的中心是YAP/Taz转录因子的控制，它由一个从 HPO激酶，在哺乳动物中为Mst1和Mst2。由于肝细胞损伤是ALD的主要驱动力 发病机制，这项探索性的R21建议的目标是确定酒精是否会减弱肝脏 再生，并通过失调肝细胞中的HPO信号通路而诱导肝脏炎症。 尽管HPO信号在限制肝细胞增殖和存活方面具有关键作用，但WE和其他人 已经确定了HPO信号通路的确切功能和分子机制 参与酒精性肝损伤，炎症和再生大多未知。因此，在这里 ALD中有关HPO信号的许多基本问题仍未得到解答。从调查中获得的知识 建议的研究将为进一步研究HPO信令的机制奠定坚实的新基础 为保护肝脏免受酒精性损伤提供了新的靶点和策略。我们未出版的 初步数据显示，在短期慢性暴饮性酒精性肝病(E1d-1B)模型中，Mst1、Mst2和Yap蛋白 水平降低了。我们还发现，浸润性巨噬细胞数量和PRO-1的表达。 在肝细胞特异性Mst1和Mst2双突变(DKO)肝脏中炎性细胞因子增加。我们 假设YAP表达减少导致肝细胞死亡和损伤增加 肝细胞再生；而Mst1和Mst2在酒精性肝细胞中的下调起作用 到慢性损伤前的肝脏炎症。在具体目标1中，我们将定义饮酒对 肝细胞中的HPO信号通路。在具体目标2中，我们将确定酒精喂养是否会抑制 通过减少肝细胞中的YAP来实现肝再生。在具体目标3中，我们将确定饮酒是否 通过减少肝细胞中的Mst1和Mst2而引起肝脏炎症。

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.