Molecular Mechanisms of Inflammation, Steatosis and Hepatic Insulin Resistance

描述（由申请人提供）：胰岛素抵抗、肝脏炎症和NAFLD是互锁的病理生理事件，但对这些异常的机制以及这些不同过程相互作用的方式知之甚少。这是一个广泛的合作应用，其中四个参与PI和实验室将集中精力研究肝脏炎症、脂肪变性和胰岛素抵抗的病因学和病理生理学。这项申请的规模很大，将侧重于四个总体具体目标。在第一个目标中，将在高脂饮食（HFD）/肥胖小鼠中进行雄心勃勃的大规模时间过程，结合系统的体外和体内测量，以揭示动态时间过程和关键转变点，从而能够发展肝胰岛素抵抗/炎症/脂肪变性。第二个目的是探索一种新的假设，该假设提出肠道微生物菌群和肠道对细菌产物的渗透性的变化触发了针对肝脏的炎症信号。这些炎症刺激物然后与肝脏中的免疫细胞相互作用，产生慢性肝脏炎症状态。第三个目标包括几个新的想法和假设，旨在描绘肝脏代谢紊乱的分子机制。这些研究将涉及跟踪免疫细胞到肝脏的行程，鉴定不同肝细胞类型的表型功能，研究胰岛素信号传导、脂肪生成/脂肪氧化、炎症中涉及的生化途径，以及鉴定由肥胖诱导的基因组基因座中的转录因子顺式和表观遗传变化。在这些研究中，将大量使用许多基因敲除小鼠的体内和体外研究。最终目的是提出转化研究，其中将从肥胖NAFLD受试者体重减轻前后获得肝活检。将在这些活检中进行细胞、生化和基因组研究，并与这些患者的体内临床数据相关联。通过这种方式，我们将能够测试从前三个目标的基础研究中学到的想法和概念与人类病理生理学的相关性。 公共卫生相关性：NAFLD与肝脏胰岛素抵抗和炎症密切相关，是美国最常见的肝病。肝脏胰岛素抵抗，炎症和脂肪变性之间相互作用的病理生理机制知之甚少，该项目应导致大大提高对这种疾病的基本理解，并有可能导致新的治疗机会。

DESCRIPTION (provided by applicant): Insulin resistance, hepatic inflammation, and NAFLD are interlocking pathophysiologic events, but the mechanisms of these abnormalities, and the ways in which these different processes interact, are poorly understood. This is a broad, collaborative application in which the four participating PI's and laboratories will concentrate their focus on the etiology and pathophysiology of hepatic inflammation, steatosis, and insulin resistance. The scale of this application is substantial and will focus on four overall specific aims. In the first aim, an ambitious, large scale time course will be undertaken in high fat diet (HFD)/obese mice, coupled with systematic in vitro and in vivo measurements to uncover the dynamic temporal time course and key transition points enabling the development of hepatic insulin resistance/inflammation/steatosis. The second aim explores a novel hypotheses which proposes that changes in intestinal microflora and gut permeability to bacterial products triggers inflammatory signals directed to the liver. These inflammatory stimuli then interact with immune cells in the liver, generating the chronic hepatic inflammatory state. The third aim encompasses several new ideas and hypotheses aimed at delineating the molecular mechanisms underlying the metabolic disturbances in the liver. These studies will involve tracking the itinerary of immune cells to the liver, identifying the phenotypic function of the different liver cell types, studies of biochemical pathways involved in insulin signaling, lipogenesis/fat oxidation, inflammation, and the identification of transcription factor cistromes and epigenetic changes in genomic loci induced by obesity. In vivo and in vitro studies in a number of knockout mice will be heavily used in the pursuit of these studies. The final aim proposes translational studies in which liver biopsies will be obtained from obese NAFLD subjects before and after weight loss. Cellular, biochemical, and genomic studies will be performed in these biopsies and correlated with the in vivo clinical data on these patients. In this way, we will be able to test the ideas and concepts learned from the basic studies in the first three aims for relevance to human pathophysiology. PUBLIC HEALTH RELEVANCE: NAFLD is closely associated with hepatic insulin resistance and inflammation and is the most common liver disease in the US. The pathophysiologic mechanisms underlying the interactions between hepatic insulin resistance, inflammation, and steatosis are poorly understood, and this project should lead to a greatly improved basic understanding of this disorder with the potential to lead to new therapeutic opportunities.