Ji Cheng, Chan Christine, Kaplowitz Neil
USC/UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, HMR-101, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
J Hepatol. 2006 Nov;45(5):717-24. doi: 10.1016/j.jhep.2006.05.009. Epub 2006 Jun 21.
BACKGROUND/AIMS: Alcohol-induced fatty liver is associated with induction of sterol response element binding proteins (SREBPs), transcription factors which regulate expression of genes of lipid synthesis. The contribution of SREBP-1c to alcohol-induced fatty liver and injury was studied.
Wild type and SREBP1c null mice were fed alcohol or control diet by intragastric infusion for 4 weeks. H&E and TUNEL staining, real-time PCR, RT-PCR, and immunoblotting were applied to analyze alcohol-induced liver injury.
ALT, plasma homocysteine, liver cholesterol, and TUNEL positive hepatocytes were increased in alcohol-fed mice as compared to control in both genotypes. Liver triglycerides were increased 4-fold in alcohol-fed wild type mice (87.2+/-7.5 vs. control 22.3+/-3.1mg/g liver) but 1.8-fold in alcohol-fed null mice (27.9+/-4 vs. control 14.5+/-3.8 mg/g liver). SREBP-2 and HMG CoA reductase were higher in the null than in wild type. Betaine feeding prevented partially the alcohol-induced changes of hepatic lipids and injury in both genotypes. mRNA of Insig-1 was reduced in both genotypes fed alcohol. No change was detected for the SREBP cleavage-activating protein (Scap) or S1P in either genotype fed alcohol.
The predominant mechanism of hepatic triglyceride accumulation in the intragastric alcohol fed mouse requires the participation of SREBP-1c. SREBP-2 regulated cholesterol accumulation still occurs.
背景/目的：酒精性脂肪肝与固醇调节元件结合蛋白（SREBPs）的诱导有关，SREBPs是调节脂质合成基因表达的转录因子。本研究探讨了SREBP-1c在酒精性脂肪肝及肝损伤中的作用。
通过灌胃法分别给予野生型和SREBP1c基因敲除小鼠酒精或对照饮食，持续4周。采用苏木精-伊红（H&E）染色、末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）染色、实时荧光定量聚合酶链反应（real-time PCR）、逆转录聚合酶链反应（RT-PCR）及免疫印迹法分析酒精诱导的肝损伤。
与对照组相比，两种基因型的酒精喂养小鼠血清谷丙转氨酶（ALT）、血浆同型半胱氨酸、肝脏胆固醇及TUNEL阳性肝细胞数量均增加。酒精喂养的野生型小鼠肝脏甘油三酯增加4倍（87.2±7.5 vs. 对照组22.3±3.1mg/g肝脏），而酒精喂养的基因敲除小鼠增加1.8倍（27.9±4 vs. 对照组14.5±3.8mg/g肝脏）。基因敲除小鼠中SREBP-2及3-羟基-3-甲基戊二酰辅酶A还原酶（HMG CoA reductase）水平高于野生型小鼠。给予甜菜碱可部分预防两种基因型小鼠酒精诱导的肝脏脂质变化及肝损伤。两种基因型的酒精喂养小鼠中胰岛素诱导基因1（Insig-1）的信使核糖核酸（mRNA）均减少。两种基因型的酒精喂养小鼠中SREBP裂解激活蛋白（Scap）或S1P均未发生变化。
灌胃酒精喂养小鼠肝脏甘油三酯蓄积的主要机制需要SREBP-1c参与。SREBP-2调节的胆固醇蓄积仍然存在。
