Phytol-induced Hepatotoxicity in Mice
Phytol-induced Hepatotoxicity in Mice
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DOI：
10.1177/0192623308330789
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发表时间：
2009-02-01
影响因子：
1.5
通讯作者：
Kier, Ann B.
中科院分区：
文献类型：
--
作者：
Mackie, John T.;Atshaves, Barbara P.;Kier, Ann B.
植酸是一种支链饱和脂肪酸，在乳制品和反刍动物脂肪中含量较高。其他一些饮食脂肪含有较低水平的植醇，吸收后很容易转化为植酸。植酸是一种过氧化体增殖物，它与核转录因子过氧化体增殖物激活受体α(PPARα)结合，诱导过氧化体和线粒体中编码脂肪酸氧化酶的基因表达。给予正常小鼠膳食植物酚(0.5%或1%)12至18天，可引起一致的PPARα介导的反应，如体重下降，肝脏重量增加，过氧化物体增殖，过氧化氢酶表达增加，肝细胞肥大和增殖。饲喂0.5%植醇的雌性小鼠和饲喂1%植醇的雄性和雌性小鼠出现中带肝细胞坏死、门脉周围肝细胞脂肪空泡化，以及肝脏植醇代谢物植酸和伯斯坦酸水平相应增加。雌性小鼠肝脏中固醇携带蛋白-x(SCP-x)的表达比雄性小鼠低5-12倍。这些结果表明，植醇可能导致小鼠选择性中带性肝细胞坏死，这是一种罕见的肝毒性损伤模式，雌性小鼠对植物酸氧化能力的增强可能反映了其氧化植酸的能力较低，因为雌性小鼠肝脏中SCP-x的表达天生较低。
Phytanic acid is a branched-chain, saturated fatty acid present in high concentrations in dairy products and ruminant fat. Some other dietary fats contain lower levels of phytol, which is readily converted to phytanic acid after absorption. Phytanic acid is a peroxisome proliferator binding the nuclear transcription factor peroxisome proliferator-activated receptor alpha (PPAR alpha) to induce expression of genes encoding enzymes of fatty acid oxidation in peroxisomes and mitochondria. Administration of dietary phytol (0.5% or 1%) to normal mice for twelve to eighteen days caused consistent PPAR alpha-mediated responses, such as lower body weights, higher liver weights, peroxisome proliferation, increased catalase expression, and hepatocellular hypertrophy and hyperplasia. Female mice fed 0.5% phytol and male and female mice fed 1% phytol exhibited midzonal hepatocellular necrosis, periportal hepatocellular fatty vacuolation, and corresponding increases in liver levels of the phytol metabolites phytanic acid and pristanic acid. Hepatic expression of sterol carrier protein-x (SCP-x) was five- to twelve-fold lower in female mice than in male mice. These results suggest that phytol may cause selective midzonal hepatocellular necrosis in mice, an uncommon pattern of hepatotoxic injury, and that the greater susceptibility of female mice may reflect a lower capacity to oxidize phytanic acid because of their intrinsically lower hepatic expression of SCP-x.