Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis
Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis
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DOI：
10.1111/j.1872-034x.2009.00494.x
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发表时间：
2009-06-01
影响因子：
4.2
通讯作者：
Horie, Yasuo
中科院分区：
文献类型：
--
作者：
Anezaki, Yumiko;Ohshima, Shigetoshi;Horie, Yasuo
非酒精性脂肪性肝病（NAFLD）被认为是一个世界性的公共卫生问题。NAFLD在男性中比在女性中更普遍。他莫昔芬是一种强效雌激素受体拮抗剂，可引起非酒精性脂肪性肝炎（NASH），这是NAFLD的一种严重形式。因此，NAFLD和NASH可能存在依赖于雌激素的性别差异。肝细胞特异性pten缺陷小鼠表现出类似于NASH的肝脏病变，被认为是NASH的临床模型。我们的目的是阐明pten缺陷小鼠肝脏病变的性别差异及其潜在机制。在40周时，对雄性和雌性pten缺陷小鼠的肝脏进行处理，测量脂质含量，基因表达分析和组织学检查。同时测定血清活性氧（ROS）水平。采用76周龄小鼠进行肿瘤负荷实验。与雄性相比，pten缺陷小鼠的肝脏脂肪变性、炎症甚至癌变在雌性小鼠中都有所减轻。女性脂肪肝的减轻归因于固醇调节元件结合蛋白1c的失活。雌性肝脏炎症通过降低ROS，增加抗氧化基因表达和减少促炎细胞因子的产生来抑制。雌性小鼠的抗癌效果，至少部分是由于肝脏中油酸与硬脂酸的比例显著降低。与男性相比，pten缺陷小鼠的肝脏病变在女性中减弱，人类NAFLD和NASH也是如此。性别差异的一些潜在机制似乎是由于依赖于雌激素的基因表达的改变。
Nonalcoholic fatty liver disease (NAFLD) is considered to be a public health problem worldwide. NAFLD is more prevalent in men than in women. Tamoxifen, a potent estrogen receptor antagonist, causes nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. Thus, there may be a sex difference that is dependent on estrogens in NAFLD and NASH. Hepatocyte-specific Pten-deficient mice exhibit hepatic lesions analogous to NASH and are considered to be a clinical model of NASH. We aimed to shed light on any sex differences in the hepatic lesions of Pten-deficient mice and the underlying mechanisms.At 40 weeks, livers from male and female Pten-deficient mice were processed for measuring lipid content, genes expression analysis, and histological examination. Level of serum reactive oxygen species (ROS) was also determined. Seventy-six-week-old mice were used in tumor burden experiments.Hepatic steatosis, inflammation, and even carcinogenesis in Pten-deficient mice were attenuated in females compared to males. Attenuated fatty liver in females was ascribed to inactivation of sterol regulatory element binding protein-1c. Hepatic inflammation in females was suppressed via decreased ROS with increased antioxidant gene expression and decreased proinflammatory cytokine production. Anti-cancer effect in female mice was, at least in part, due to the significantly lower ratio of oleic to stearic acid in the liver.Hepatic lesions in Pten-deficient mice were attenuated in females compared to males, as were human NAFLD and NASH. Some of the underlying mechanisms in sex difference appeared to be due to the change of gene expression, dependent on estrogens.