Relationship between sudden death syndrome of alcohol drinker and the role of bone marrow-derived stellate cells in alcohol-induced fatty liver

饮酒者猝死综合征与骨髓源性星状细胞在酒精性脂肪肝中作用的关系

基本信息

批准号：
20590680
负责人：
FUJIMIYA Tatsuya
金额：
$ 3.08万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

Chronic alcohol consumption activates hepatic stellate cells (HSCs) and cause fatty degeneration in the liver. However, the origin of HSCs and the mechanism of fatty changes of the liver have not been fully elucidated. Here, we examined the roles of bone marrow-derived cells (BMDCs) in a mouse model with chronic alcohol consumption. We performed bone marrow transplantation from transgenic mice expressing green fluorescence protein (GFP) to female wild-type and ROSA mice and treated them with ethanol (EtOH) for 8 or 16 wk. GFP-expressing BMDCs increased in the liver with EtOH treatment in a time-dependent manner. In response to excess alcohol consumption, ~68% of the BMDCs became activated HSCs in that they expressed α-smooth muscle actin. Meanwhile, ~67% and ~66% of these BMDCs expressed Tnf-α and transforming growth factor (Tgf)-β1, respectively, and the activities were further supported by the excessive mRNA expression of Tnf-α and Tgf-β1 in RT-PCR, respectively. Cell fusion occurs between BMDCs and nonparenchymal cells but scarcely occurs between BMDCs and hepatocytes, demonstrated by double staining of β-gal/GFP and further supported by the Y-chromosome staining. The EtOH withdrawal normalized most of the abnormalities produced by chronic alcohol consumption. These results indicate that excess alcohol consumption stimulates both the homing of HSCs from the bone marrow and their profibrogenic cytokine production in a mouse model of alcohol-induced fatty liver disease.

慢性饮酒会激活肝星状细胞（HSC）并导致肝脏脂肪变性，然而，HSC 的起源和肝脏脂肪变化的机制尚未完全阐明。在此，我们研究了骨髓来源的作用。我们将表达绿色荧光蛋白（GFP）的转基因小鼠的骨髓移植到雌性野生型和 ROSA 小鼠中，并用乙醇处理它们。 (EtOH) 8 或 16 周，EtOH 处理后肝脏中表达 GFP 的 BMDC 以时间依赖性的方式增加。同时，这些 BMDC 分别表达 Tnf-α 和转化生长因子 (Tgf)-β1，且活性进一步增强。 RT-PCR 中 Tnf-α 和 Tgf-β1 的过量 mRNA 表达分别支持了 BMDC 和非实质细胞之间发生细胞融合，但 BMDC 和肝细胞之间几乎不发生细胞融合，这通过 β-gal/GFP 双重染色得到证明并得到进一步支持。通过 Y 染色体染色，乙醇戒断使长期饮酒产生的大部分异常正常化。这些结果表明，过量饮酒会刺激 HSC 从骨骼中归巢。酒精诱导的脂肪肝疾病小鼠模型中的骨髓及其促纤维细胞因子的产生。