Fujiwara Kentaro, Mori Keiji, Kaneko Yoko S, Nakashima Akira, Nagasaka Akio, Itoh Mitsuyasu, Ota Akira
Division of Endocrinology and Metabolism, Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake 470-1192, Japan.
Biochim Biophys Acta. 2004 Feb 24;1670(3):181-98. doi: 10.1016/j.bbagen.2003.12.004.
Tetrahydrobiopterin is an essential cofactor for nitric oxide synthase (NOS). This study was undertaken to examine the effects of intraperitoneally injected lipopolysaccharide on tetrahydrobiopterin biosynthesis in murine white and brown adipose tissues. Tetrahydrobiopterin content, catalytic activity and mRNA expression level of GTP cyclohydrolase I (GCH), rate-controlling enzyme in de novo biosynthesis of tetrahydrobiopterin, in both adipose tissues were up-regulated by 500-microg lipopolysaccharide at 6 h after the injection. On the contrary, treatment of 3T3-L1 adipocytes with lipopolysaccharide alone did not affect GCH mRNA expression level, whereas the combination of lipopolysaccharide, tumor necrosis factor (TNF)-alpha, and interferon gamma induced the increase in expression levels of GCH mRNA and CD14 mRNA. Collectively, our results showed that tetrahydrobiopterin biosynthesis can be augmented by increased GCH activity caused by a synergistic effect of lipopolysaccharide and cytokines in white and brown adipose tissues. These observations support the view that tetrahydrobiopterin biosynthesis in the adipose tissues is a target of inflammatory events triggered by peripheral LPS injection.
四氢生物蝶呤是一氧化氮合酶（NOS）的一种必需辅因子。本研究旨在探讨腹腔注射脂多糖对小鼠白色和棕色脂肪组织中四氢生物蝶呤生物合成的影响。注射500微克脂多糖后6小时，两种脂肪组织中四氢生物蝶呤的含量、催化活性以及四氢生物蝶呤从头生物合成的限速酶GTP环化水解酶I（GCH）的mRNA表达水平均上调。相反，单独用脂多糖处理3T3-L1脂肪细胞并不影响GCH mRNA表达水平，而脂多糖、肿瘤坏死因子（TNF）-α和干扰素γ联合使用则诱导GCH mRNA和CD14 mRNA表达水平升高。总的来说，我们的结果表明，脂多糖和细胞因子的协同作用导致GCH活性增加，从而增强白色和棕色脂肪组织中四氢生物蝶呤的生物合成。这些观察结果支持了这样一种观点，即脂肪组织中的四氢生物蝶呤生物合成是外周注射脂多糖引发的炎症事件的一个靶点。
