Schnabl Bernd, Czech Barbara, Valletta Daniela, Weiss Thomas S, Kirovski Georgi, Hellerbrand Claus
Department of Internal Medicine I, University Hospital Regensburg, Germany.
Int J Clin Exp Pathol. 2011;4(7):661-6. Epub 2011 Sep 22.
Hepatocellular lipid accumulation is a hallmark of non-alcoholicfatty liver disease (NAFLD), which encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and ultimately cirrhosis. Zinc finger protein 267 (ZNF267) belongs to the family of Kruppel-like transcription factors, which regulate diverse biological processes that include development, proliferation, and differentiation. We have previously demonstrated that ZNF267 expression is up-regulated in liver cirrhosis and is further increased in hepatocellular carcinoma (HCC). Here, we analyzed the expression of ZNF267 in tissue specimens of NAFLD patients and found a significant up-regulation compared to normal liver tissue. Noteworthy, ZNF267 mRNA was already significantly increased in steatotic liver tissue without inflammation. In line with this, incubation of primary human hepatocytes with palmitic acid induced a dose-dependent lipid accumulation and corresponding dose-dependent ZNF267 induction in vitro. Furthermore, hepatocellular lipid accumulation induced formation of reactive oxygen species (ROS), and also chemically induced ROS formation increased ZNF267 mRNA expression. In summary with previous findings, which revealed ZNF267 as pro-fibrogenic and pro-cancerogenic factor in chronic liver disease, the present study further suggests ZNF267 as promising therapeutic target particularly for NAFLD patients. In addition, it further indicates that hepatic steatosis per se has pathophysiological relevance and should not be considered as benign.
肝细胞脂质蓄积是非酒精性脂肪性肝病（NAFLD）的一个标志，NAFLD涵盖了从单纯性脂肪变性到非酒精性脂肪性肝炎（NASH）并最终发展为肝硬化的一系列病变。锌指蛋白267（ZNF267）属于Kruppel样转录因子家族，该家族调控包括发育、增殖和分化在内的多种生物学过程。我们之前已经证明ZNF267在肝硬化中表达上调，在肝细胞癌（HCC）中进一步升高。在此，我们分析了NAFLD患者组织标本中ZNF267的表达，发现与正常肝组织相比有显著上调。值得注意的是，在无炎症的脂肪变性肝组织中ZNF267 mRNA就已经显著增加。与此一致的是，用棕榈酸孵育原代人肝细胞在体外诱导了剂量依赖性的脂质蓄积以及相应的剂量依赖性ZNF267诱导。此外，肝细胞脂质蓄积诱导了活性氧（ROS）的形成，化学诱导的ROS形成也增加了ZNF267 mRNA表达。与之前揭示ZNF267作为慢性肝病促纤维化和促癌因子的研究结果一致，本研究进一步表明ZNF267是一个有前景的治疗靶点，尤其对于NAFLD患者。此外，它还进一步表明肝脂肪变性本身具有病理生理学相关性，不应被视为良性病变。
