Hepatic CCAAT/enhancer binding protein α mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice
Hepatic CCAAT/enhancer binding protein α mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice
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DOI：
10.1210/me.2004-0213
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发表时间：
2004-11-01
影响因子：
--
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
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作者：
Matsusue, K;Gavrilova, O;Gonzalez, FJ
CCAAT/增强子结合蛋白α(C/EBPalpha)是新生儿糖代谢的关键因子，传统的C/EBPalpha缺失型小鼠由于严重的低血糖和肝糖原积累不足而无法在出生后第一天存活。为了阐明C/EBPalpha在瘦素缺陷型小鼠(ob/ob)肝脏中的作用，在白蛋白启动子(AlbCre)的控制下，利用C/EBPalpha等位基因和Cre重组酶，建立了ob/ob背景下的C/EBPalpha肝缺失小鼠(ob/ob-C/EBPalpha/Cre(+))。与没有AlbCre转基因(ob/ob-C/EBPalpha/Cre(+))的同等小鼠相比，ob/ob小鼠C/EBPalpha缺陷小鼠的肝脏甘油三酯含量显著降低。脂肪合成酶、乙酰辅酶A羧基酶、硬脂酰辅酶A脱饱和酶1和三磷酸腺苷柠檬酸裂解酶基因在ob/ob-C/EBPalpha/Cre(+)小鼠肝脏中的表达显著降低。高碳水化合物饮食诱导这些造脂基因导致ob/ob-C/EBPalpha/Cre(+)小鼠脂肪肝的恶化和肝脏大小、肝脏甘油三酯和胆固醇含量的增加，但在ob/OBC/EBPalpha/Cre(+)小鼠中没有。由于胰岛素分泌减少，肝脏C/EBPalpha表达不足导致高血糖加重。综上所述，这些结果表明，肝脏C/EBPalpha通过间接调节胰岛素的分泌，在促进ob/ob小鼠的脂肪生成和血糖稳态中起着关键作用。
CCAAT/enhancer binding protein alpha (C/EBPalpha)is a critical factor in glucose metabolism in the neonate as revealed by conventional C/EBPalpha-null mice that do not survive beyond the first day after birth because of severe hypoglycemia and a deficiency in hepatic glycogen accumulation. To elucidate the function of C/EBPalpha in leptin-deficient mouse (ob/ob) liver, a C/EBPalpha-liver null mouse on an ob/ob background (ob/ob-C/EBPalpha/Cre(+)) was produced using a floxed C/EBPalpha allele and Cre recombinase under control of the albumin promoter (AlbCre). The C/EBPalpha-deficient liver in ob/ob mice had significantly decreased triglyceride content compared with equivalent mice lacking the AlbCre transgene (ob/ob-C/EBPalpha/Cre(+)). Expression of genes involved in lipogenesis including fatty acid synthase, acetyl-coenzyme A carboxylase, stearoyl-coenzyme A desaturase 1 and ATP-citrate lyase dramatically decreased in ob/ob-C/EBPalpha/Cre(+) mouse liver. Induction of these lipogenic genes by a high-carbohydrate diet caused an exacerbation in the development of fatty liver and an increase in liver size, hepatic triglyceride, and cholesterol contents in ob/ob-C/EBPalpha/Cre(+) mice but not in ob/obC/EBPalpha/Cre(+) mice. Deficiency in hepatic C/EBPalpha expression caused an exacerbation of hyperglycemia because of decreased insulin secretion. Taken together, these results indicate that hepatic C/EBPalpha plays a critical role in the acceleration of lipogenesis in ob/ob mice and in glucose homeostasis by the indirect regulation of insulin secretion.