Sheth Sonal S, Castellani Lawrence W, Chari Soumya, Wagg Cory, Thipphavong Christopher K, Bodnar Jackie S, Tontonoz Peter, Attie Alan D, Lopaschuk Gary D, Lusis Aldons J
Department of Human Genetics, Medicine, Molecular Biology Institute, University of California, Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
J Lipid Res. 2005 Jan;46(1):123-34. doi: 10.1194/jlr.M400341-JLR200. Epub 2004 Nov 1.
Through a positional cloning approach, the thioredoxin-interacting protein gene (Txnip) was recently identified as causal for a form of combined hyperlipidemia in mice (Bodnar, J. S., A. Chatterjee, L. W. Castellani, D. A. Ross, J. Ohmen, J. Cavalcoli, C. Wu, K. M. Dains, J. Catanese, M. Chu, S. S. Sheth, K. Charugundla, P. Demant, D. B. West, P. de Jong, and A. J. Lusis. 2002. Positional cloning of the combined hyperlipidemia gene Hyplip1. Nat. Genet. 30: 110-116). We now show that Txnip-deficient mice in the fed state exhibit a metabolic profile similar to fasted mice, including increased levels of plasma ketone bodies and free fatty acids, decreased glucose, and increased hepatic expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and acyl-CoA oxidase. Dramatic differences in the expression of key metabolic enzymes were also observed in other tissues, and the fat-to-muscle ratio of Txnip-deficient mice was increased by approximately 40%. We demonstrate an effect of Txnip on the redox status, as the Txnip-deficient mice in the fed state had a significant increase in the ratio of NADH to NAD(+). Surprisingly, we observed that Txnip-deficient mice and wild-type mice had similar levels of thioredoxin activity, suggesting that the effects of Txnip deficiency may be mediated in part by other interactions. These results indicate a role for Txnip in the metabolic response to feeding and the maintenance of the redox status.
通过定位克隆方法，硫氧还蛋白相互作用蛋白基因（Txnip）最近被确定为小鼠中一种复合型高脂血症的病因（博德纳，J.S.，A.查特吉，L.W.卡斯特拉尼，D.A.罗斯，J.奥门，J.卡瓦科利，C.吴，K.M.戴恩斯，J.卡塔内塞，M.朱，S.S.谢思，K.查鲁贡德拉，P.德曼特，D.B.韦斯特，P.德容，以及A.J.卢西斯。2002年。复合型高脂血症基因Hyplip1的定位克隆。《自然遗传学》30: 110 - 116）。我们现在表明，处于进食状态的Txnip基因缺陷型小鼠呈现出与禁食小鼠相似的代谢特征，包括血浆酮体和游离脂肪酸水平升高、血糖降低，以及过氧化物酶体增殖物激活受体γ共激活因子 - 1α、磷酸烯醇式丙酮酸羧激酶、葡萄糖 - 6 - 磷酸酶和酰基辅酶A氧化酶的肝脏表达增加。在其他组织中也观察到关键代谢酶表达的显著差异，并且Txnip基因缺陷型小鼠的脂肪与肌肉比例增加了约40%。我们证明了Txnip对氧化还原状态的影响，因为处于进食状态的Txnip基因缺陷型小鼠中NADH与NAD⁺的比例显著增加。令人惊讶的是，我们观察到Txnip基因缺陷型小鼠和野生型小鼠具有相似水平的硫氧还蛋白活性，这表明Txnip缺陷的影响可能部分由其他相互作用介导。这些结果表明Txnip在对进食的代谢反应和氧化还原状态的维持中发挥作用。
