Signaling-pathway-based preventative strategies for alcoholic liver disease

描述(申请人提供)：酒精性肝损伤是一种常见的肝脏疾病，部分原因是脂代谢紊乱和炎症。酒精性肝病(ALD)的发展经历了四个病理阶段：脂肪变性、脂肪性肝炎、纤维化和肝硬化。脂质堆积的严重程度与肝脏毒性的发展有很强的联系。肝脏脂肪堆积的增加增强了肠道中产生的外源物质和内毒素加强酒精性肝炎和纤维化的能力，这可能是通过增加炎症信号来实现的，而炎症信号依赖于Kupffer细胞/肝细胞的相互作用和其他免疫细胞。过氧化物酶体增殖物激活受体-a(PPARa)在调节肝脏脂肪酸分解代谢中起重要作用。鉴于脂肪堆积在ALD病因中的重要性，与表达功能性PPARa的小鼠相比，Ppara缺失的小鼠表现出加重的ALD也就不足为奇了。与调节脂质分解代谢的PPARa相反，最近研究表明，PPAR？/d还通过诱导胰岛素诱导基因-1(Insig-1)的表达来抑制肝脏脂肪生成，Insig-1是一种内质网蛋白，可以抑制SREBP的激活。初步数据将证明，PPAR？/d可以预防毒素对肝脏的损害，支持PPAR？/d也可以预防ALD的假设，这一想法迄今尚未得到检验。再加上强有力的证据表明PPARa和PPAR？/d具有强大的抗炎活性，本应用的重点是阐明PPARa和PPAR？/d调节肝脏脂质堆积和肝脏炎症的机制，这两条已知的途径在介导ALD中起关键作用。特殊目的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/或先前存在的ALD的适宜性，以及PPARa和PPAR？/d调节肝脏酒精诱导的毒性的机制。在这些模型中，PPAR激动性的评估将通过比较基因表达和靶向代谢组学与肝脏病理来评估，以机械地描绘在ALD模型中PPARa和PPAR？/d如何调节肝脂代谢。特异性目标2将使用创新的转基因小鼠模型来确定炎症是否在促进ALD的过程中调节PPAR依赖的肝脂积聚，并区分体细胞介导的炎症(例如肝细胞)和免疫细胞介导的炎症(例如。库普弗细胞、中性粒细胞、淋巴细胞)。这项应用的结果将确定，结合PPARa和PPAR？/d的配体激活和/或抑制p38依赖的炎症是否会改进以坚实的机制基础预防或治疗ALD的方法。这项申请结合了艾伯特·J·福奈斯博士的实验室(乔治城大学)和杰弗里·M·彼得斯博士(宾夕法尼亚州立大学)的独特专业知识和经验，以定义对ALD至关重要的PPAR调节和炎症依赖诱导机制。 公共卫生相关性：酒精性肝损伤是一种常见的肝病，具有重要的健康和社会经济后果，部分原因是脂代谢和炎症调节失调。这项申请结合了艾伯特·J·福纳斯博士的实验室(乔治城大学)和杰弗里·M·彼得斯博士(宾夕法尼亚州立大学)的独特专业知识和经验，以定义对酒精性肝病至关重要的脂代谢调节和炎症依赖诱导机制。结果将改进预防或治疗酒精性肝病的方法，具有坚实的机制基础。

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.