CCAAT/Enhancer-binding protein β deletion reduces adiposity, hepatic steatosis, and diabetes in Leprdb/db mice
CCAAT/Enhancer-binding protein β deletion reduces adiposity, hepatic steatosis, and diabetes in Leprdb/db mice
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DOI：
10.1074/jbc.m701329200
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发表时间：
2007-05-25
影响因子：
4.8
通讯作者：
Friedman, Jacob E.
中科院分区：
文献类型：
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作者：
Schroeder-Gloeckler, Jill M.;Rahman, Shaikh Mizanoor;Friedman, Jacob E.
CCAAT/增强子结合蛋白β(C/EBPβ)在启动脂肪组织的脂肪生成和肝脏的糖异生中起着关键作用，但C/EBPβ在肝脏脂肪生成中的作用尚不清楚。在这里，我们展示了在Leprdb/db小鼠中C/EBPβ失活可以减轻肥胖、脂肪肝和糖尿病。除了脂肪生成受阻外，C/EB beta(-/-)x Lepr(db/db)小鼠的肝脏还显著降低了甘油三酯含量和造脂酶活性。在LepR(db/db)小鼠中，c/EBPβ缺失下调了PPAR-激活受体γ2(PPAR-Gamma 2)和硬脂酰辅酶A去饱和酶-1，上调了PPARα，而不依赖SREBP1c。相反，野生型小鼠的C/EBPβ过表达增加了PPAR-2和硬脂酰辅酶A去饱和酶-1mRNA和肝脏甘油三酯的含量。在FAO细胞中，过表达肝脏抑制形式的C/EBPβ或C/EBPβRNA干扰可减弱棕榈酸酯诱导的甘油三酯积聚，并降低体内肝脏中PPARγ2和甘油三酯的水平。瘦素和抗糖尿病药物二甲双胍显著下调肝细胞中C/EBPβ的表达，而脂肪酸则上调C/EBPβ的表达。这些数据提供了新的证据，将C/EBPβ表达与脂肪生成和能量平衡联系起来，对肥胖症和脂肪肝的治疗具有重要意义。
CCAAT/enhancer-binding protein beta (C/EBP beta) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/ EBP beta in hepatic lipogenesis remains undefined. Here we show that C/EBP beta inactivation in Leprdb/ db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EB beta(-/-) x Lepr(db/db) mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBP beta deletion in Lepr(db/db) mice down-regulated peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2) and stearoyl-CoA desaturase-1 and up-regulated PPAR alpha independent of SREBP1c. Conversely, C/EBP beta overexpression in wild-type mice increased PPAR gamma 2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBP beta or C/EBP beta RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPAR gamma 2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBP beta expression in hepatocytes, whereas fatty acids up-regulate C/EBP beta expression. These data provide novel evidence linking C/EBP beta expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.