Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599, USA.
Hepatology. 2012 Jul;56(1):130-9. doi: 10.1002/hep.25641. Epub 2012 Jun 6.
Alcoholic liver injury is a major public health issue worldwide. Even though the major mechanisms of this disease have been established over the past decades, little is known about genetic susceptibility factors that may predispose individuals who abuse alcoholic beverages to liver damage and subsequent pathological conditions. We hypothesized that a panel of genetically diverse mouse strains may be used to examine the role of endoplasmic reticulum (ER) stress and one-carbon metabolism in the mechanism of interindividual variability in alcoholic liver injury. We administered alcohol (up to 27 mg/kg/d) in a high-fat diet using an intragastric intubation model for 28 days to male mice from 14 inbred strains (129S1/SvImJ, AKR/J, BALB/cJ, BALB/cByJ, BTBR T+tf/J, C3H/HeJ, C57BL/10J, DBA/2J, FVB/NJ, KK/HIJ, MOLF/EiJ, NZW/LacJ, PWD/PhJ, and WSB/EiJ). Profound interstrain differences (more than 3-fold) in alcohol-induced steatohepatitis were observed among the strains in spite of consistently high levels of urine alcohol that were monitored throughout the study. We found that ER stress genes were induced only in strains with the most liver injury. Liver glutathione and methyl donor levels were affected in all strains, albeit to a different degree. The most pronounced effects that were closely associated with the degree of liver injury were hyperhomocysteinemia and strain-dependent differences in expression patterns of one-carbon metabolism-related genes.
Our data demonstrate that strain differences in alcohol-induced liver injury and steatosis are striking and independent of alcohol exposure and the most severely affected strains exhibit major differences in the expression of ER stress markers and genes of one-carbon metabolism.
酒精性肝损伤是全球范围内的一个主要公共卫生问题。尽管过去几十年已经确定了这种疾病的主要机制，但对于可能使滥用酒精的个体易患肝损伤和随后的病理状态的遗传易感性因素知之甚少。我们假设一组遗传多样化的小鼠品系可用于研究内质网（ER）应激和一碳代谢在个体间酒精性肝损伤变异性机制中的作用。我们使用胃内插管模型，以高脂肪饮食给来自 14 个近交系（129S1/SvImJ、AKR/J、BALB/cJ、BALB/cByJ、BTBR T+tf/J、C3H/HeJ、C57BL/10J、DBA/2J、FVB/NJ、KK/HIJ、MOLF/EiJ、NZW/LacJ、PWD/PhJ 和 WSB/EiJ）的雄性小鼠施用酒精（每天高达 27mg/kg），持续 28 天。尽管在整个研究过程中始终监测尿液中的酒精水平，但观察到各品系之间酒精性肝炎的严重程度存在显著的品系间差异（超过 3 倍）。我们发现仅在肝脏损伤最严重的品系中诱导 ER 应激基因。尽管所有品系的肝谷胱甘肽和甲基供体水平均受到影响，但程度不同。与肝损伤程度最密切相关的最显著影响是高同型半胱氨酸血症和一碳代谢相关基因表达模式的品系依赖性差异。
我们的数据表明，酒精诱导的肝损伤和脂肪变性的品系差异非常显著，与酒精暴露无关，受影响最严重的品系在 ER 应激标志物和一碳代谢相关基因的表达方面存在显著差异。
