Yang Shiqi, Koteish Ayman, Lin Huizhi, Huang Jiawen, Roskams Tania, Dawson Valina, Diehl Anna Mae
Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Hepatology. 2004 Feb;39(2):403-11. doi: 10.1002/hep.20082.
Hepatic steatosis may have a generally benign prognosis, either because most hepatocytes are not significantly injured or mechanisms to replace damaged hepatocytes are induced. To determine the relative importance of these mechanisms, we compared hepatocyte damage and replication in ethanol-fed and ob/ob mice with very indolent fatty liver disease to that of healthy control mice and PARP-1(-/-) mice with targeted disruption of the DNA repair enzyme, poly(ADP-ribose) polymerase. Compared to the healthy controls, both groups with fatty livers had significantly higher serum alanine aminotransferase values, hepatic mitochondrial H(2)O(2) production, and hepatocyte oxidative DNA damage. A significantly smaller proportion of the hepatocytes from fatty livers entered S phase when cultured with mitogens. Moreover, this replicative senescence was not reversed by treating cultured hepatocytes with agents (i.e., betaine or leptin) that improve liver disease in intact ethanol-fed or leptin-deficient mice. Hepatocytes from PARP1(-/-) mice also had more DNA damage and reduced DNA synthesis in response to mitogens. However, neither mice with fatty livers nor PARP-1-deficient mice had atrophic livers. All of the mice with senescent mature hepatocytes exhibited hepatic accumulation of liver progenitor (oval) cells and oval cell numbers increased with the demand for hepatocyte replacement. Therefore, although hepatic oxidant production and damage are generally increased in fatty livers, expansion of hepatic progenitor cell populations helps to compensate for the increased turnover of damaged mature hepatocytes. In conclusion, these results demonstrate that induction of mechanisms to replace damaged hepatocytes is important for limiting the progression of fatty liver disease.
肝脂肪变性的预后通常可能是良性的，这要么是因为大多数肝细胞未受到显著损伤，要么是因为诱导了替代受损肝细胞的机制。为了确定这些机制的相对重要性，我们将患有非常惰性的脂肪性肝病的乙醇喂养小鼠和ob/ob小鼠的肝细胞损伤和复制情况与健康对照小鼠以及靶向破坏DNA修复酶聚（ADP - 核糖）聚合酶的PARP - 1(-/-)小鼠进行了比较。与健康对照相比，两组脂肪肝小鼠的血清丙氨酸氨基转移酶值、肝线粒体H(2)O(2)产生量以及肝细胞氧化性DNA损伤均显著更高。当用有丝分裂原培养时，来自脂肪肝的肝细胞进入S期的比例显著更小。此外，用能改善完整乙醇喂养或瘦素缺乏小鼠肝病的药物（即甜菜碱或瘦素）处理培养的肝细胞并不能逆转这种复制性衰老。PARP1(-/-)小鼠的肝细胞在有丝分裂原刺激下也有更多的DNA损伤和DNA合成减少。然而，脂肪肝小鼠和PARP - 1缺陷小鼠均没有肝萎缩。所有具有衰老成熟肝细胞的小鼠均表现出肝祖（卵圆）细胞在肝脏中的积累，并且卵圆细胞数量随着对肝细胞替代的需求增加而增加。因此，尽管脂肪肝中肝脏氧化剂的产生和损伤通常会增加，但肝祖细胞群体的扩增有助于补偿受损成熟肝细胞增加的更新率。总之，这些结果表明诱导替代受损肝细胞的机制对于限制脂肪性肝病的进展很重要。
