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

长期饮酒会激活肝星状细胞(HSCs)，导致肝脏脂肪变性。然而，HSCs的来源和肝脏脂肪变化的机制尚未完全阐明。在这里，我们研究了骨髓来源的细胞(BMDCs)在慢性饮酒小鼠模型中的作用。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，并用乙醇(Etoh)处理它们8或16 wk。乙醇处理组大鼠肝脏中表达GFP的BMDCs呈时间依赖性增加。在过量饮酒后，约68%的BMDCs通过表达α-平滑肌肌动蛋白而被激活。同时，约67%和66%的BMDCs表达肿瘤坏死因子-α和转化生长因子-β-1，RT-α和转化生长因子-β1的高表达进一步支持了这一活性。β-Gal/GFP双重染色证实BMDCs与非实质细胞之间存在细胞融合，而BMDCs与肝细胞之间几乎不融合。Etoh的戒断使长期饮酒产生的大部分异常恢复了正常。这些结果表明，在酒精诱导的脂肪肝小鼠模型中，过量饮酒刺激来自骨髓的HSCs归巢及其促纤维化细胞因子的产生。

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.