Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice
Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice
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DOI：
10.1007/s11745-003-1093-x
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发表时间：
2003-05-01
期刊：
影响因子：
1.9
通讯作者：
Onishi, S
中科院分区：
文献类型：
--
作者：
Egawa, T;Toda, K;Onishi, S
他莫昔芬是一种有效的雌激素拮抗剂，肝脂肪变性是辅助他莫昔芬治疗乳腺癌的常见并发症。过氧化物酶体、微粒体和线粒体中的脂肪酸P氧化受损导致雌激素缺乏时大量肝脂肪变性的进展。这种损害虽然是潜伏的，但可能是严重的：目前美国约有3%的普通人群患有与肥胖和高脂血症相关的非酒精性脂肪性肝炎。因此，在本研究中，我们试图恢复受损的肝脏FA P-氧化通过管理一种新的他汀类药物，匹伐他汀，芳香酶缺陷（Ar-/-）小鼠内在雌激素合成缺陷。Ar-/-小鼠肝脏的北方印迹分析显示，参与FA β氧化的必需酶的mRNA表达显著恢复，如过氧化物酶体中的极长脂肪酰辅酶A合成酶、过氧化物酶体脂肪酰辅酶A氧化酶和中链酰基辅酶A脱氢酶。在Ar-/-小鼠中观察到的重度肝脂肪变性基本消退。在FA β-氧化活性的体外试验中获得了一致的结果。这些发现表明，匹伐他汀能够通过过氧化物酶体增殖物激活受体-α-介导的信号通路恢复体内受损的FA β-氧化，并且足以改善内源性雌激素缺乏小鼠的严重肝脂肪变性。Lipids 38，519 - 523（2003年5月）中的论文编号L9263。
Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA P-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA P-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen. Paper no. L9263 in Lipids 38, 519-523 (May 2003).