Dobashi Kazushige, Araki Shunsuke, Kubo Kazuyasu, Kawagoe Rinko, Yamamoto Yukiyo, Shirahata Akira
Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
Life Sci. 2008 Jan 2;82(1-2):85-90. doi: 10.1016/j.lfs.2007.10.013. Epub 2007 Nov 1.
Preadipocytes are considered to play a role in adipose tissue inflammation in obesity. The purpose of this study was to determine whether hydroxymethylglutaryl-CoA reductase inhibitor (statin) modulates the nitric oxide (NO) production via inducible NO synthase (iNOS) in preadipocytes. Undifferentiated 3T3-L1 cells, a model of preadipocytes, significantly produced NO by the treatment with the combination of lipopolysaccharide (L), tumor necrosis factor-alpha (T) and interferon-gamma (I). Pre-incubation with simvastatin, a lipophilic statin, or pravastatin, a hydrophilic one, dose-dependently inhibited the NO production in the LTI-treated cells. The effect of simvastatin was offset by mevalonate or geranylgeranyl pyrophosphate (GGPP) but not by squalene. The mRNA level for iNOS paralleled the NO production. The nuclear factor-kappaB (NF-kappaB) was activated by the LTI-treatment, and was inhibited by addition of simvastatin or pravastatin. Mevalonate or GGPP completely offset the effect of simvastatin. Simvastatin or pravastatin also decreased the LTI-stimulated interleukin-6 (IL-6) secretion. These effects of pravastatin were relatively weak compared with those of simvastatin. Y27632, an inhibitor of Rho kinase, also inhibited the LTI-induced NF-kappaB activation and iNOS expression, and decreased the production of NO and IL-6 in 3T3-L1 preadipocytes. These results suggest that statins, especially lipophilic types, inhibit induction of iNOS by inhibiting the small GTP-binding protein signal in preadipocytes.
前脂肪细胞被认为在肥胖相关的脂肪组织炎症中发挥作用。本研究的目的是确定羟甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）是否通过诱导前脂肪细胞中的一氧化氮合酶（iNOS）来调节一氧化氮（NO）的产生。未分化的3T3-L1细胞是前脂肪细胞的一种模型，经脂多糖（L）、肿瘤坏死因子-α（T）和干扰素-γ（I）联合处理后能显著产生NO。用亲脂性他汀类药物辛伐他汀或亲水性他汀类药物普伐他汀预孵育，可剂量依赖性地抑制LTI处理细胞中的NO产生。辛伐他汀的作用可被甲羟戊酸或香叶基香叶基焦磷酸（GGPP）抵消，但不能被角鲨烯抵消。iNOS的mRNA水平与NO产生平行。核因子-κB（NF-κB）被LTI处理激活，并被添加辛伐他汀或普伐他汀抑制。甲羟戊酸或GGPP完全抵消了辛伐他汀的作用。辛伐他汀或普伐他汀也降低了LTI刺激的白细胞介素-6（IL-6）分泌。与辛伐他汀相比，普伐他汀的这些作用相对较弱。Rho激酶抑制剂Y27632也抑制LTI诱导的NF-κB激活和iNOS表达，并降低3T3-L1前脂肪细胞中NO和IL-6的产生。这些结果表明，他汀类药物，尤其是亲脂性类型，通过抑制前脂肪细胞中的小GTP结合蛋白信号来抑制iNOS的诱导。
