mTORC1 activation and alcoholic liver injury

总结 mTORC 1激活与酒精性肝损伤 关键词：酒精性脂肪肝，mTORC 1，DEPTOR，ER应激，SREBP-1 酒精中毒是西方社会肝病的主要原因。肝脂肪变性（脂肪肝）是一种早期 酒精性肝病的可逆阶段。然而，未经检查的肝脂肪变性可发展为 不可逆的脂肪性肝炎、纤维化、肝硬化和最终的肝细胞癌。酒精性脂肪肝 疾病（AFLD）的发生归因于内质网（ER）应激信号传导的激活。但 AFLD中肝ER应激的分子机制尚未完全清楚。虽然大 哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）通路的鉴定已取得进展 由于mTORC 1通路是一种重要的代谢物，因此对mTORC 1通路在酒精性肝中的体内作用知之甚少。 病理生理学我们最近的研究表明，通过NAD依赖的mTORC 1抑制肝脏， 去乙酰化酶SIRT 1抑制肝ER应激，下调脂肪生成，从而改善肝硬化。 糖尿病小鼠的脂肪变性。令人兴奋的初步数据显示，肝脏mTORC 1在慢性暴食中被激活， 酒精喂养的小鼠，这伴随着ER应激的诱导，脂肪生成的激活，以及肝脏 脂肪变性重要的是，新的研究表明，与mTORC 1激活一致，肝脏中的 DEPTOR是一种新发现的mTORC 1内源性抑制剂，在酒精喂养的小鼠中减少。更好地 了解酒精性肝病的发病机制，并为酒精性肝病制定替代治疗策略。 我们的中心假设是mTORC 1在酒精性脂肪肝中起着关键作用， 促进肝脏ER应激和刺激脂肪生成。提出了两个具体目标：1） 表征mTORC 1在酒精诱导的ER应激和脂肪生成中的功能和机制作用， 2）确定mTORC 1抑制是否改善小鼠中的肝脂肪变性和ER应激 酒精性脂肪肝为了响应NIAAA计划（PA-10-094），题为“酒精中的压力途径 诱导的器官损伤和保护”，拟议的研究将确定慢性酒精暴露是否 通过mTORC 1组分如DEPTOR、TSC 1/2或Raptor导致mTORC 1活化， 加速肝脂肪变性和ER应激的发展。基于细胞的体外机制研究以及 因为将利用操纵肝mTORC 1活性的体内药理学和遗传学方法。 这些拟议研究的创新方面包括：（1）对mTORC 1作为一种新的调节剂的新见解， 酒精诱导的内质网应激途径和脂肪肝;（2）DEPTOR依赖性抑制的新概念， mTORC 1通过减轻内质网应激和抑制脂肪生成改善酒精性脂肪肝和肝损伤; (3)DEPTOR/mTORC 1作为AFLD和ER应激相关肝脏治疗干预的新靶点 疾病，如癌症。我们的长期目标是阐明AFLD的病理机制， 确定在酒精性肝病的早期和可逆阶段进行干预的新分子靶点， 开发一种潜在的AFLD标记物，以帮助早期诊断和预后。

Summary mTORC1 activation and alcoholic liver injury Key words: alcohol fatty liver, mTORC1, DEPTOR, ER stress, and SREBP-1 Alcoholism is a leading cause of liver disease in Western societies. Hepatic steatosis (fatty liver) is an early and reversible stage of alcoholic liver disease. However, unchecked hepatic steatosis can develop into irreversible steatohepatitis, fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Alcoholic fatty liver disease (AFLD) is attributed to the activation of endoplasmic reticulum (ER) stress signaling. However, the molecular mechanisms underlying hepatic ER stress in AFLD are not fully understood. Although great progress has been made in the identification of mammalian target of rapamycin complex 1 (mTORC1) pathway components, relatively little is known about the in vivo role of the mTORC1 pathway in alcoholic liver pathophysiology. Our recent studies demonstrate that hepatic inhibition of mTORC1 by the NAD-dependent deacetylase SIRT1 suppresses hepatic ER stress, downregulates lipogenesis, and thereby ameliorates hepatic steatosis in diabetic mice. Exciting preliminary data show that hepatic mTORC1 is activated in chronic binge alcohol-fed mice, which is accompanied by induction of ER stress, activation of lipogenesis, and hepatic steatosis. Importantly, new studies suggest that consistent with mTORC1 activation, hepatic levels of DEPTOR, a newly identified endogenous inhibitor of mTORC1, are reduced in alcohol-fed mice. To better understand the pathogenesis of alcoholic liver disease and develop alternative therapeutic strategies for the disease, our CENTRAL HYPOTHESIS is that mTORC1 plays a key role in alcoholic fatty liver disease by promoting hepatic ER stress and stimulating lipogenesis. Two specific aims are proposed: 1) To characterize the functional and mechanistic role of mTORC1 in alcohol-induced ER stress and lipogenesis in hepatocytes; 2) To determine whether mTORC1 inhibition ameliorates hepatic steatosis and ER stress in mice with alcoholic fatty liver. In response to the NIAAA program (PA-10-094) entitled “stress pathways in alcohol induced organ injury and protection”, the proposed studies will determine whether chronic alcohol exposure results in mTORC1 activation via mTORC1 components such as DEPTOR, TSC1/2 or Raptor and thereby accelerates the development of hepatic steatosis and ER stress. In vitro cell-based mechanistic studies as well as in vivo pharmacologic and genetic approaches of manipulating hepatic mTORC1 activity will be utilized. Innovative aspects of these proposed studies include: (1) new insight into mTORC1 as a novel regulator of alcohol-induced ER stress pathways and fatty liver; (2) the novel concept that DEPTOR-dependent inhibition of mTORC1 ameliorates alcoholic fatty liver and liver injury by relieving ER stress and inhibiting lipogenesis; (3) DEPTOR/mTORC1 as new targets for the therapeutic interventions of AFLD and ER stress-related liver diseases such as cancer. Our long-term objective is to elucidate the pathological mechanisms of AFLD, to identify novel molecular targets for intervention at this early and reversible stage of alcoholic liver disease, and to develop a potential marker of AFLD to aid early diagnosis and prognosis.