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，但调节这一转变的机制在我们对纤维发生的理解中存在关键空白。显然，细胞因子如TNF1和TGF2起着关键作用，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几乎在乙醇诱导的肝损伤的每个阶段都是一致的主题。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，慢性乙醇暴露后被抑制的L-FABP异构体已被证明可以调节肝脏抗th2细胞因子il - 12的表达。此外，FABP5亚型与IL17调控有关，IL17是一种最近被证明与酒精性肝病有关的细胞因子。因此，FABP代表了肝脏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验证脂质结合蛋白FABP， L-FABP和mal1 （FABP5）调节肝脏Th2细胞因子表达以响应乙醇的中心假设。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FABPs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，乙醇致敏小鼠确实加剧了肝脏Th2反应。因此，我们将表征暴露于乙醇的小鼠肝脏Th1/Th2反应T细胞依赖性肝炎。我们的实验数据还表明，FABP的表达在乙醇的作用下发生了改变。在后续的目标中，将确定FABPs在Th1/Th2细胞因子调节中的作用。最后，我们将评估L-FABP-/-和FABP5-/-在慢性乙醇性肝损伤，特别是乙醇性肝纤维化中的作用。其基本原理是，由于脂肪代谢与肝纤维化的转变是整体相关的，我们假设FABP缺失的小鼠更容易受到慢性乙醇引起的纤维化的影响。总之，我们期望这些实验结果能够代表脂质代谢机制与肝纤维化发生之间的重要机制联系。

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.