Signaling-pathway-based preventative strategies for alcoholic liver disease

描述（由申请人提供）：酒精性肝损伤是一种常见的肝脏疾病，部分原因是脂质代谢失调和炎症。酒精性肝病（ALD）的发展经历四个病理阶段：脂肪变性、脂肪性肝炎、纤维化和肝硬化。脂质蓄积的严重程度与肝毒性的发生之间存在密切联系。肝脏脂质蓄积增加可增强肠道中产生的外源性物质和内毒素增强酒精性肝炎和纤维化的能力，可能通过增加炎症信号传导，这取决于枯否细胞/肝细胞相互作用和其他免疫细胞。过氧化物酶体增殖物激活受体-α（PPARa）在调节肝脏脂肪酸代谢中具有重要作用。考虑到脂质积累在ALD病因学中的重要性，与表达功能性PPARa的小鼠相比，PPARa缺失小鼠表现出恶化的ALD并不令人惊讶。与调节脂质代谢的PPARa相反，最近显示，PPARa/d还通过诱导胰岛素诱导基因-1（Insig-1）（一种抑制SREBP激活的内质网蛋白）的表达来抑制肝脏脂肪生成，从而调节肝脏脂质代谢。初步数据将确定，PPAR <$/d可以保护肝脏免受毒素的损害，支持PPAR <$/d也可以保护肝脏免受ALD的假设，这是一个迄今为止尚未研究过的想法。结合PPARa和PPARb/d具有有效抗炎活性的强有力证据，本申请的重点在于阐明PPARa和PPARb/d调节肝脂质积累和肝炎症的机制，这是介导ALD的两种已知关键途径。具体目标1将使用Ppara-null和Pparb/d-null小鼠模型来区分靶向这些受体以抑制早期和/或预先存在的ALD的适用性以及PPARa和PPARa/d调节肝脏酒精诱导的毒性的机制。将通过比较基因表达和靶向代谢组学特征与肝脏病理学来评价这些模型中的PPAR激动作用，以机械地描述在ALD模型中PPARa和PPARa/d如何调节肝脏脂质代谢。具体目标2将使用创新的和新型的转基因小鼠模型来确定炎症是否调节促进ALD的PPAR依赖性肝脂质积累，并区分体细胞介导的炎症（例如肝细胞）与免疫细胞介导的炎症（例如，枯否细胞、中性粒细胞、淋巴细胞）。本申请的结果将确定结合PPARa和PPARd的配体活化和/或p38依赖性炎症的抑制是否会改善预防或治疗ALD的方法，并具有坚实的机制原理。该应用程序结合了Albert J. Fornace博士实验室（乔治敦大学）和Jeffrey M. Peters（Penn州立大学）的研究，以确定对ALD至关重要的PPAR调节和炎症依赖性诱导机制。 公共卫生相关性：酒精性肝损伤是一种常见的肝脏疾病，具有重要的健康和社会经济后果，部分原因是脂质代谢失调和炎症。该应用程序结合了Albert J. Fornace博士实验室（乔治敦大学）和Jeffrey M. Peters（宾夕法尼亚州立大学）的研究，以确定对酒精性肝病至关重要的脂质代谢调节和炎症依赖性诱导机制。结果将改善方法，以预防或治疗酒精性肝病与坚实的机械原理。

DESCRIPTION (provided by applicant): Alcohol-induced liver damage is a common liver disease that is due in part to dysregulated lipid metabolism and inflammation. Alcoholic liver disease (ALD) progresses through four pathological stages: steatosis, steatohepatitis, fibrosis and cirrhosis. There is a strong link between the severity of lipid accumulation and the development of liver toxicity. Increased hepatic lipid accumulation enhances the ability of xenobiotics and endotoxins produced in the gut to potentiate alcoholic hepatitis and fibrosis, likely by increased inflammatory signaling, which is dependent on Kupffer cell/hepatocyte interactions and other immune cells. Peroxisome proliferator-activated receptor-a (PPARa) has a central role in regulating fatty acid catabolism in liver. Given the significance of lipid accumulation in the etiology of ALD, it is not surprising that Ppara-null mice exhibit exacerbated ALD as compared to mice expressing a functional PPARa. In contrast to PPARa that regulates lipid catabolism, it was recently shown that PPAR¿/d also modulates hepatic lipid metabolism by inhibiting hepatic lipogenesis by inducing expression of insulin-induced gene-1 (Insig-1), an endoplasmic reticulum protein that inhibits SREBP activation. Preliminary data will establish that PPAR¿/d can protect against liver damage by toxins, supporting the hypothesis that PPAR¿/d will also protect against ALD, an idea that has not been examined to date. Coupled with strong evidence that PPARa and PPAR¿/d have potent anti- inflammatory activities, the focus of this application is on elucidating the mechanisms by which PPARa and PPAR¿/d regulate hepatic lipid accumulation and hepatic inflammation, two known pathways critical in mediating ALD. Specific aim 1 will use the Ppara-null and Pparb/d-null mouse models to distinguish between the suitability of targeting these receptors to inhibit early and/or pre-existing ALD and the mechanisms by which PPARa and PPAR¿/d modulate hepatic alcohol-induced toxicity. Evaluation of PPAR agonism in these models will be evaluated by comparing gene expression and targeted metabolomic profiles with liver pathology to mechanistically delineate how PPARa and PPAR¿/d regulate hepatic lipid metabolism in an ALD model. Specific aim 2 will use innovative and novel transgenic mouse models to determine if inflammation modulates PPAR-dependent hepatic lipid accumulation in promoting ALD and to distinguish between somatic cell- mediated inflammation (e.g. hepatocyte) versus immune cell-mediated inflammation (e.g,. Kupffer cell, neutrophils, lymphocytes). Results from this application will determine whether combining ligand activation of PPARa and PPAR¿/d and/or inhibition of p38-dependent inflammation will improve approaches to prevent or treat ALD with a solid mechanistic rationale. This application combines the unique expertise and experience of Dr. Albert J. Fornace's laboratory (Georgetown University) and Dr. Jeffrey M. Peters (Penn State University) to define the PPAR regulatory and inflammation-dependent inducing mechanisms that are essential for ALD. PUBLIC HEALTH RELEVANCE: Alcohol-induced liver damage is a common liver disease with important health and socioeconomic consequences that is due in part to dysregulated lipid metabolism and inflammation. This application combines the unique expertise and experience of Dr. Albert J. Fornace's laboratory (Georgetown University) and Dr. Jeffrey M. Peters (Penn State University) to define lipid metabolism regulatory and inflammation-dependent inducing mechanisms that are essential for alcoholic liver disease. Results will improve approaches to prevent or treat alcoholic liver disease with a solid mechanistic rationale.