Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
J Hepatol. 2012 Oct;57(4):837-43. doi: 10.1016/j.jhep.2012.05.013. Epub 2012 May 26.
BACKGROUND & AIMS: The tumor suppressor p53 is a primary sensor of stressful stimuli, controlling a number of biologic processes. The aim of our study was to examine the roles of p53 in non-alcoholic steatohepatitis (NASH).
Male wild type and p53-deficient mice were fed a methionine- and choline-deficient diet for 8 weeks to induce nutritional steatohepatitis. mRNA expression profiles in normal liver samples and liver samples from patients with non-alcoholic liver disease (NAFLD) were also evaluated.
Hepatic p53 and p66Shc signaling was enhanced in the mouse NASH model. p53 deficiency suppressed the enhanced p66Shc signaling, decreased hepatic lipid peroxidation and the number of apoptotic hepatocytes, and ameliorated progression of nutritional steatohepatitis. In primary cultured hepatocytes, transforming growth factor (TGF)-β treatment increased p53 and p66Shc signaling, leading to exaggerated reactive oxygen species (ROS) accumulation and apoptosis. Deficient p53 signaling inhibited TGF-β-induced p66Shc signaling, ROS accumulation, and hepatocyte apoptosis. Furthermore, expression levels of p53, p21, and p66Shc were significantly elevated in human NAFLD liver samples, compared with results obtained with normal liver samples. Among NAFLD patients, those with NASH had significantly higher hepatic expression levels of p53, p21, and p66Shc compared with the group with simple steatosis. A significant correlation between expression levels of p53 and p66Shc was observed.
p53 in hepatocytes regulates steatohepatitis progression by controlling p66Shc signaling, ROS levels, and apoptosis, all of which may be regulated by TGF-β. Moreover, p53/p66Shc signaling in the liver appears to be a promising target for the treatment of NASH.
肿瘤抑制因子 p53 是应激刺激的主要传感器，控制着许多生物过程。本研究的目的是研究 p53 在非酒精性脂肪性肝炎（NASH）中的作用。
雄性野生型和 p53 缺陷型小鼠喂食蛋氨酸和胆碱缺乏饮食 8 周，以诱导营养性脂肪性肝炎。还评估了正常肝组织样本和非酒精性肝病（NAFLD）患者肝组织样本中的 mRNA 表达谱。
在小鼠 NASH 模型中，肝 p53 和 p66Shc 信号增强。p53 缺陷抑制了增强的 p66Shc 信号，减少了肝脂质过氧化和凋亡的肝细胞数量，并改善了营养性脂肪性肝炎的进展。在原代培养的肝细胞中，转化生长因子（TGF）-β处理增加了 p53 和 p66Shc 信号，导致活性氧（ROS）积累和细胞凋亡增加。p53 信号缺陷抑制了 TGF-β诱导的 p66Shc 信号、ROS 积累和肝细胞凋亡。此外，与正常肝组织样本相比，人 NAFLD 肝组织样本中 p53、p21 和 p66Shc 的表达水平显著升高。与单纯脂肪变性组相比，NASH 组患者肝组织中 p53、p21 和 p66Shc 的表达水平显著升高。观察到 p53 和 p66Shc 表达水平之间存在显著相关性。
肝细胞中的 p53 通过控制 p66Shc 信号、ROS 水平和凋亡来调节脂肪性肝炎的进展，所有这些都可能受到 TGF-β的调节。此外，肝脏中的 p53/p66Shc 信号似乎是治疗 NASH 的一个有前途的靶点。
