Hepatology：抑癌因子控制了非酒精性脂肪性肝炎的发展

近日，来自日本庆应义塾大学医学院的研究人员发现，在人类及老鼠体内，p53/p66Shc介导的信号促进了非酒精性脂肪性肝炎(NASH)的发展。相关研究成果于5月28日在线发表在Journal of Hepatology上。

p53基因是一种抑癌基因，是细胞生长周期中的负调节因子，与细胞周期的调控、DNA修复、细胞分化、细胞凋亡等重要的生物学功能有关。p53基因的突变(缺失)是人类肿瘤的常见事件，与肿瘤的发生、发展有关。一般认为，p53的过表达与肿瘤的转移、复发及不良预后相关。

在这项研究里，为了阐明非酒精性脂肪性肝炎中p53的作用，研究人员给予了野生型及p53缺陷型雄鼠以缺乏甲硫氨酸及胆碱的食物，连续喂养八周后诱导得到了营养性脂肪性肝炎模型。随后，他们评估了正常肝组织及非酒精性肝病(NAFLD)患者的mRNA表达谱。

研究发现，在小鼠NASH模型体内，肝细胞内p53及p66Shc信号增强。而p53缺陷则抑制了增强的p66Shc信号，减少了肝内脂质过氧化反应以及凋亡的肝细胞数目，改善了营养性脂肪性肝炎。

在原代培养的肝细胞，转化生长因子(TGF)-β处理后，他们发现，p53及p66Shc信号增加，结果导致了显著的活性氧(ROS)累积及细胞凋亡。而p53缺陷则抑制了TGF-β诱导的p66Shc信号、ROS积聚、以及肝细胞凋亡。

此外，对比于正常肝组织标本，人NAFLD肝脏标本内p53、p21以及p66Shc的表达水平被显著的提升。在NAFLD患者中，对比于单纯脂肪变性群体，那些具有NASH的人群具有更高的肝内p53、p21以及p66Shc的表达水平。这表明p53及p66Sh表达水平之间存在着显著的关联。

总的来说，在肝细胞内，p53通过控制p66Shc信号、ROS水平以及细胞凋亡，调节了脂肪性肝炎的进展。而且，这些过程都可能是被TGF-β所参与调节的。此外，Toshifumi Hibi表示，该研究结果表明p53/p66Shc将能够成为一个有潜力的靶点来治疗非酒精性脂肪性肝炎。

doi: 10.1016/j.jhep.2012.05.013
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p53/p66Shc–mediated signaling contributes to the progression of nonalcoholic steatohepatitis in humans and mice

Kengo Tomita, Takahiro Suzuki, Tetsuya Oshikawa, Hirokazu Yokoyama, Katsuyoshi Shimamura, Kiyoshi Nishiyama, Norikazu Mataki, Rie Irie, Yoshikiyo Okada, Chie Kurihara, Hirotoshi Ebinuma, Hidetsugu Saito, Ippei Shimizu, Yohko Yoshida, Ryota Hokari, Kazuo Sugiyama, Kazuo Hatsuse, Junji Yamamoto, Takanori Kanai, Soichiro Miura, Toshifumi Hibi.

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 nonalcoholic steatohepatitis (NASH).Male wild-type and p53-deficient mice were fed a methionine- and choline-deficient diet for eight weeks to induce nutritional steatohepatitis. mRNA expression profiles in normal liver samples and liver samples from patients with nonalcoholic liver disease (NAFLD) were also evaluated.Hepatic p53 and p66Shc signaling were 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 the 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.