Hepatic lymphocytes and fatty liver disease

肝淋巴细胞与脂肪肝

基本信息

批准号：
7880474
负责人：
MICHAEL D WHEELER
金额：
$ 21.53万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-10 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7880474
关键词：
Academic Research Enhancement Awards Acute Address Adipose tissue Alcoholic Liver Diseases Animal Model Animals Area Award Binding Proteins Biochemistry Characteristics Chronic Collagen Concanavalin A Data Diet Environment Equilibrium Ethanol Exposure to Extracellular Matrix FABP5 gene Faculty Fatty Liver Fibrosis Fostering Functional disorder Future Goals Hepatic Hepatic Fibrogenesis Hepatic Stellate Cell Hepatitis Hepatocellular Damage Hepatocyte Hour IL17 gene Immune Inflammatory Injury Institution Interleukin-12 Knockout Mice Link Lipid Binding Lipids Liquid substance Liver Liver Fibrosis Liver diseases Lymphocyte Mediating Mentorship Metabolism Mind Modeling Mus Pathogenesis Pathology Phenotype Play Production Protein Isoforms Regulation Reporting Research Research Personnel Role Signal Transduction Staging Steatohepatitis Students T cell response T-Lymphocyte Testing Training Universities Work alcohol effect alcohol exposure alcohol response base choline deficient diet cytokine design fatty acid-binding proteins feeding fibrogenesis hepatotoxin improved lipid metabolism macrophage non-alcoholic fatty liver nonalcoholic steatohepatitis novel protein expression public health relevance research study response success transcription factor

项目摘要

DESCRIPTION (provided by applicant): Early alcoholic liver disease is characterized by an increase lipid accumulation, pro-inflammatory cytokine production and hepatocellular damage, or steatohepatitis. The transition from steatohepatitis to fibrosis involves the activation of hepatic stellate cells and production of collagen, but the mechanisms regulating this transition represent critical gaps in our understanding of fibrogenesis. Clearly, cytokines such as TNF1 and TGF2 play critical roles, and emerging evidence suggests that Th2 cytokines, though not sufficient to produce a fibrotic response, are necessary. The relationship between lipid accumulation and cytokine production, however, is a consistent theme in nearly every stage of ethanol induced liver injury. There have been a number of reports linking a number of different fatty acid binding proteins (FABP), lipid transporters involved in lipid signaling and metabolism, to the regulation of cytokine expression. Specifically, the L-FABP isoform, which is suppressed after chronic ethanol exposure, has been shown to regulate hepatic IL12 expression, an anti-Th2 cytokine. Moreover, the FABP5 isoform is linked to IL17 regulation, a cytokine which was recently shown to be involved alcoholic liver disease. Thus, FABP represents an important mechanistic link between the accumulation of lipid in liver and cytokine production. The experiments outlined in this proposal will test the central hypothesis that lipid binding proteins FABP, L-FABP and mal1 (FABP5) regulate hepatic Th2 cytokine expression in response to ethanol. Here, we'll use mice lacking the liver isoform of FABP (L-FABP-/-) and the adipose/macrophage-specific FABP (FABP5-/-) to specifically address this question. We will also employ models of acute ethanol exposure and chronic Leiber-DeCarli liquid/ ethanol diet to address the role of FABPs in cytokine regulation as well as liver pathogenesis. Our pilot data suggest indeed ethanol sensitizes mice exacerbated a hepatic Th2 response. Thus we will characterize the hepatic Th1/Th2 response T cell dependent hepatitis in mice exposed to ethanol. Our pilot data also suggest that FABP expression is altered in response to ethanol. In the subsequent aims, the role of FABPs in Th1/Th2 cytokine regulation will be determined. Lastly, the role of L-FABP-/- and FABP5-/- in chronic ethanol induced liver injury, in particular ethanol induced liver fibrosis, will be assessed. The rationale is that since that fat metabolism and the transition to liver fibrosis are integrally connected, we hypothesize FABP null mice are more susceptible to fibrosis caused by chronic ethanol. In conclusion, we expect the results of these experiments to represent important mechanistic links between the mechanisms of lipid metabolism and hepatic fibrogenesis. PUBLIC HEALTH RELEVANCE: The accumulation of lipid in the liver is an early and critically important pathological characteristic of several liver diseases including both alcoholic liver disease and non-alcoholic steatohepatitis. Liver fibrosis is a progressive stage of chronic liver disease where excess collagen and extracellular matrix is produced. The mechanisms regulating the transition from steatohepatitis to fibrosis are unknown. Here, we will investigate the role of T lymphocytes and the production of T cell derived cytokines in fibrogenesis.

描述（由申请人提供）：早期酒精性肝病的特征是脂质积累增加、促炎细胞因子产生和肝细胞损伤或脂肪性肝炎。从脂肪性肝炎到纤维化的转变涉及肝星状细胞的激活和胶原蛋白的产生，但调节这种转变的机制代表了我们对纤维化的理解中的关键差距。显然，TNF1 和 TGF2 等细胞因子发挥着关键作用，新出现的证据表明 Th2 细胞因子虽然不足以产生纤维化反应，但却是必要的。然而，脂质积累和细胞因子产生之间的关系是乙醇引起的肝损伤的几乎每个阶段的一致主题。已有许多报道将许多不同的脂肪酸结合蛋白（FABP）、参与脂质信号传导和代谢的脂质转运蛋白与细胞因子表达的调节联系起来。具体来说，L-FABP 亚型在长期接触乙醇后受到抑制，已被证明可以调节肝脏 IL12（一种抗 Th2 细胞因子）的表达。此外，FABP5 亚型与 IL17 调节有关，IL17 是一种细胞因子，最近被证明与酒精性肝病有关。因此，FABP 代表了肝脏中脂质积累和细胞因子产生之间的重要机制联系。本提案中概述的实验将检验脂质结合蛋白 FABP、L-FABP 和 mal1 (FABP5) 响应乙醇调节肝脏 Th2 细胞因子表达的中心假设。在这里，我们将使用缺乏 FABP 肝脏亚型 (L-FABP-/-) 和脂肪/巨噬细胞特异性 FABP (FABP5-/-) 的小鼠来专门解决这个问题。我们还将采用急性乙醇暴露和慢性 Leiber-DeCarli 液体/乙醇饮食模型来研究 FABP 在细胞因子调节和肝脏发病机制中的作用。我们的试验数据表明，乙醇确实使小鼠变得敏感，并加剧了肝脏 Th2 反应。因此，我们将表征暴露于乙醇的小鼠的肝脏 Th1/Th2 反应 T 细胞依赖性肝炎。我们的试验数据还表明 FABP 表达会因乙醇而改变。在后续目标中，将确定 FABP 在 Th1/Th2 细胞因子调节中的作用。最后，将评估L-FABP-/-和FABP5-/-在慢性乙醇诱导的肝损伤，特别是乙醇诱导的肝纤维化中的作用。基本原理是，由于脂肪代谢和向肝纤维化的转变是紧密相连的，我们假设 FABP 缺失小鼠更容易受到慢性乙醇引起的纤维化。总之，我们期望这些实验的结果能够代表脂质代谢机制和肝纤维发生之间的重要机制联系。公众健康相关性：肝脏中脂质的积累是包括酒精性肝病和非酒精性脂肪性肝炎在内的多种肝脏疾病的早期且极其重要的病理特征。肝纤维化是慢性肝病的进展阶段，会产生过量的胶原蛋白和细胞外基质。调节脂肪性肝炎向纤维化转变的机制尚不清楚。在这里，我们将研究 T 淋巴细胞和 T 细胞衍生细胞因子的产生在纤维发生中的作用。