Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes
Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes
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DOI：
10.1172/jci200317223
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发表时间：
2003-03-01
影响因子：
15.9
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
Matsusue, K;Haluzik, M;Gonzalez, FJ
为了阐明 PPARgamma 在瘦素缺陷小鼠 (ob/ob) 肝脏中的功能，使用 floxed PPARgamma 等位基因 PPARgamma(fl/fl) 和白蛋白启动子 (AlbCre) 控制下的 Cre 重组酶产生了 ob/ob 背景上的 PPARgamma 肝缺失小鼠 ob/ob-PPARgamma(fl/fl)AlbCre(+)。 ob/ob-PPARgamma(fl/fl)AlbCre(+) 小鼠的肝脏有外显子 2 的缺失以及相应的全长 PPARgamma mRNA 和蛋白质的损失。与缺乏 AlbCre 转基因的同等小鼠 (ob/ob-PPARgamma(fl/fl)AlbCre(-)) 相比，ob/ob 小鼠缺乏 PPARgamma 的肝脏较小，甘油三酯 (TG) 含量显着降低。 ob/ob-PPARgamma(fl/fl)AlbCre(+)小鼠的肝脂肪生成基因、脂肪酸合酶、乙酰辅酶A羧化酶和硬脂酰辅酶A去饱和酶-1的信使RNA水平降低，并且ob/ob-PPARgamma(fl/fl)AlbCre(+)小鼠的血清TG和FFA水平显着高于对照小鼠 ob/ob-PPARgamma(fl/fl)AlbCre(-) 小鼠。与非肥胖 Cre(-) 小鼠的肝脏相比，罗格列酮治疗加剧了 ob/ob-PPARgamma(fl/fl)AlbCre(-) 小鼠的脂肪肝；罗格列酮对 ob/ob-PPARgamma(fl/fl)AlbCre(+) 小鼠没有作用。由于肌肉和脂肪的胰岛素敏感性降低，肝脏 PPARgamma 的缺乏进一步加剧了 ob/ob 小鼠糖尿病的严重程度。这些数据表明，肝脏 PPARgamma 在脂肪变性糖尿病小鼠的 TG 含量调节以及血糖稳态和胰岛素抵抗中发挥着关键作用。
To elucidate the function of PPARgamma in leptin-deficient mouse (ob/ob) liver, a PPARgamma liver-null mouse on an ob/ob background, ob/ob-PPARgamma(fl/fl)AlbCre(+), was produced using a floxed PPARgamma allele, PPARgamma(fl/fl), and Cre recombinase under control of the albumin promoter (AlbCre). The liver of ob/ob-PPARgamma(fl/fl)AlbCre(+) mice had a deletion of exon 2 and a corresponding loss of full-length PPARgamma mRNA and protein. The PPARgamma-deficient liver in ob/ob mice was smaller and had a dramatically decreased triglyceride (TG) content compared with equivalent mice lacking the AlbCre transgene (ob/ob-PPARgamma(fl/fl)AlbCre(-)). Messenger RNA levels of the hepatic lipogenic genes, fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase-1, were reduced in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice, and the levels of serum TG and FFA in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice were significantly higher than in the control ob/ob-PPARgamma(fl/fl)AlbCre(-) mice. Rosiglitazone treatment exacerbated the fatty liver in ob/ob-PPARgamma(fl/fl)AlbCre(-) mice compared with livers from nonobese Cre(-) mice; there was no effect of rosiglitazone in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice. The deficiency of hepatic PPARgamma further aggravated the severity of diabetes in ob/ob mice due to decreased insulin sensitivity in muscle and fat. These data indicate that hepatic PPARgamma plays a critical role in the regulation of TG content and in the homeostasis of blood glucose and insulin resistance in steatotic diabetic mice.