Hepatic CCAAT/enhancer binding protein α mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice

被引:69
作者
Matsusue, K
Gavrilova, O
Lambert, G
Brewer, HB
Ward, JM
Inoue, Y
LeRoith, D
Gonzalez, FJ
机构
[1] NCI, NIH, Lab Metab, Bethesda, MD 20892 USA
[2] NIAID, Comparat Med Branch, Bethesda, MD 20892 USA
[3] NHLBI, Mol Dis Branch, Bethesda, MD 20892 USA
[4] NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA
[5] Hop Hotel Dieu, INSERM, Unite 539, F-44000 Nantes, France
关键词
D O I
10.1210/me.2004-0213
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:2751 / 2764
页数:14
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