Hepatic lymphocytes and fatty liver disease

描述（由申请人提供）：早期酒精性肝病的特征是脂质蓄积增加、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活化和胶原蛋白的产生，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空白。显然，细胞因子如TNF 1和TGF 2发挥关键作用，新出现的证据表明，Th 2细胞因子，虽然不足以产生纤维化反应，是必要的。然而，在乙醇诱导的肝损伤的几乎每个阶段，脂质积累和细胞因子产生之间的关系是一致的主题。已经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。特别是，L-FABP同种型，在慢性乙醇暴露后被抑制，已被证明可调节肝IL 12表达，一种抗Th 2细胞因子。此外，FABP 5同种型与IL 17调节有关，IL 17是一种最近显示与酒精性肝病有关的细胞因子。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mal 1（FABP 5）响应于乙醇调节肝脏Th 2细胞因子表达的中心假设。在这里，我们将使用缺乏肝脏同种型FABP（L-FABP-/-）和脂肪/巨噬细胞特异性FABP（FABP 5-/-）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/乙醇饮食模型来解决FABP在细胞因子调节以及肝脏发病机制中的作用。我们的试验数据表明，乙醇确实使小鼠敏感，加剧了肝脏Th 2反应。因此，我们将表征肝脏Th 1/Th 2应答T细胞依赖性肝炎小鼠暴露于乙醇。我们的试验数据还表明，FABP的表达改变响应乙醇。在随后的目标中，将确定FABPs在Th 1/Th 2细胞因子调节中的作用。最后，将评估L-FABP-/-和FABP 5-/-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。其基本原理是，由于脂肪代谢和向肝纤维化的转变是整体相关的，我们假设FABP基因敲除小鼠更容易受到慢性乙醇引起的纤维化的影响。总之，我们期望这些实验的结果代表脂质代谢和肝纤维化发生机制之间的重要机制联系。 公共卫生相关性：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的几种肝病的早期和至关重要的病理特征。肝纤维化是慢性肝病的进行性阶段，其中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，我们将调查的作用，T淋巴细胞和T细胞衍生的细胞因子的生产在纤维化。

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.