Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice.
Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice.
复制标题
胆汁胆固醇分泌的加速可恢复肥胖 db/db 小鼠的血糖控制并减轻高甘油三酯血症。
DOI：
10.1161/atvbaha.113.302355
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Graf,GregoryA
中科院分区：
文献类型：
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作者：
Su,Kai;Sabeva,NadezhdaS;Wang,Yuhuan;Liu,Xiaoxi;Lester,JoshuaD;Liu,Jingjing;Liang,Shuang;Graf,GregoryA
最近的研究支持胆固醇在肥胖和非酒精性脂肪肝的发展中的作用。缺乏ABCG 5 ABCG 8（G5 G8）甾醇转运蛋白的小鼠胆汁胆固醇分泌减少，并且在高脂饮食的挑战下更容易发生脂肪变性、肝胰岛素抵抗和血糖控制丧失。我们假设，加速G5 G8介导的胆汁胆固醇分泌将纠正这些表型在肥胖mice.Approach和ResultsObese（db/db）的男性和他们的瘦同窝仔被管理的鸡尾酒控制腺病毒或腺病毒载体编码ABCG 5和ABCG 8（AdG 5G 8）。病毒给药后三天，测定脂质和葡萄糖稳态的测量值，并收集组织进行生化分析。AdG 5G 8增加胆汁胆固醇和粪便固醇消除。与接受对照腺病毒的小鼠相比，表达G5 G8的肥胖小鼠空腹血糖和甘油三酯下降，葡萄糖耐量改善。这些变化与肝脏中磷酸化真核起始因子2α和c-Jun N-末端激酶的减少有关，表明内质网应激减轻。磷酸化胰岛素受体和蛋白激酶B增加，表明肝脏胰岛素信号传导恢复。然而，有没有减少肝脏甘油三酯后3天的治疗period.ConclusionsAccelerating胆汁胆固醇分泌恢复血糖控制和降低血浆甘油三酯在obesedb/db小鼠。
ObjectiveRecent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice.Approach and ResultsObese (db/db) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. AdG5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2α and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period.ConclusionsAccelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obesedb/dbmice.