Beneficial direct adipotropic actions of pitavastatin in vitro and their manifestations in obese mice
Beneficial direct adipotropic actions of pitavastatin in vitro and their manifestations in obese mice
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DOI：
10.1016/j.atherosclerosis.2010.04.019
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发表时间：
2010-09-01
期刊：
影响因子：
5.3
通讯作者：
Kohno, Masakazu
中科院分区：
文献类型：
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作者：
Ishihara, Yasuhiro;Ohmori, Koji;Kohno, Masakazu
目的：肥胖患者心血管并发症的预防通常包括他汀类药物治疗并存的血脂异常。在此，我们研究了临床相关剂量的匹伐他汀对脂肪功能障碍和insulin resistance.Methods的影响：我们用10-100 ng/ml匹伐他汀处理3 T3-L1前脂肪细胞，从分化开始（第0天）到第8天（分化/成熟期）或从第8天到第16天（成熟后期）。随后，我们管理匹伐他汀（6.2毫克/天/公斤）7周龄的雌性KKAy小鼠6周;未经处理的KKAy小鼠作为肥胖controls.Results：匹伐他汀损害既不脂肪生成也不脂联素的表达在分化/成熟阶段。在后成熟阶段，匹伐他汀防止过度的甘油三酯积累，这与减弱葡萄糖转运蛋白-4的表达，并剂量依赖性上调脂肪酶敏感性脂肪酶的表达。脂联素/纤溶酶原激活物-1比值的下降也受到剂量依赖性抑制。在KKAy小鼠中，Coulter计数器分析显示匹伐他汀治疗显著降低（16.8%）宫旁脂肪垫中肥大脂肪细胞（直径>150 μ m）的频率，其总重量保持不变。相应地，匹伐他汀处理的KKAy小鼠的血浆脂联素显著高于未处理的KKAy小鼠（12.5 +/-3.8 μ g/ml vs. 8.3 +/-1.5 μ g/ml，p < 0.05）。此外，在匹伐他汀治疗的KKAy小鼠中，腹膜内胰岛素后的时间-葡萄糖曲线下的面积减少了16%（p < 0.05，与未治疗的对照组相比）。在肥胖模型中，这些作用可能通过预防脂肪细胞肥大和脂肪细胞因子失调而有助于改善胰岛素敏感性。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Objective: Prevention of cardiovascular complications in obese patients frequently includes statin administration for coexisting dyslipidemia. Herein, we investigated the impacts of pitavastatin at clinically relevant doses on adipose dysfunction and insulin resistance.Methods: We treated 3T3-L1 preadipocytes with 10-100 ng/ml pitavastatin from initiation of differentiation (Day 0) to Day 8 (differentiation/maturation phase) or from Day 8 to Day 16 (post-maturation phase). Subsequently, we administered pitavastatin (6.2 mg/day/kg) to 7-week-old female KKAy mice for 6 weeks; untreated KKAy mice served as obese controls.Results: Pitavastatin impaired neither lipogenesis nor adiponectin expression during the differentiation/maturation phase. During the post-maturation phase, pitavastatin prevented excessive triglyceride accumulation, which was associated with attenuated glucose transporter-4 expression, and dose-dependently upregulated hormone-sensitive lipase expression. Decrements in the adiponectin/plasminogen activator-1 ratio were also dose-dependently inhibited. In KKAy mice, Coulter counter analyses revealed that pitavastatin treatment significantly decreased (by 16.8%) the frequency of hypertrophic adipocytes (>150 mu m in diameter) in parametrial adipose pads, of which total weight remained unaltered. Correspondingly, plasma adiponectin was significantly higher in pitavastatin-treated KKAy mice than in the untreated KKAy mice (12.5 +/- 3.8 mu g/ml vs. 8.3 +/- 1.5 mu g/ml, p < 0.05). Moreover, the area under the time-glucose curve after intraperitoneal insulin was decreased by 16% in pitavastatin-treated KKAy mice (p < 0.05 vs. untreated controls).Conclusions: Pitavastatin did not impair differentiation/maturation of preadipocytes and prevented their deterioration with hypertrophy after maturation at clinical concentrations in vitro. These effects likely contributed to improved insulin sensitivity, in an obese model, via prevention of adipocyte hypertrophy and adipocytokine dysregulation. (C) 2010 Elsevier Ireland Ltd. All rights reserved.