Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
Molecular Imaging Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
PeerJ. 2023 Apr 3;11:e15191. doi: 10.7717/peerj.15191. eCollection 2023.
The effects of hypoxia inducible factor-2α (HIF-2α) deficiency on liver fibrosis have not been demonstrated in a fibrosis model induced by carbon tetrachloride (CCl). We aimed to examine whether hepatocyte-specific HIF-2α deletion could ameliorate CCl-induced liver fibrosis in mice.
Hepatocyte-specific HIF-2α knockout mice were created using an albumin promoter-driven Cre recombinase. HIF-2α knockout (KO) mice and floxed control wild-type (WT) mice were fed a normal diet (ND) and received either twice weekly intraperitoneal injections of CCl solution (CCl dissolved in olive oil) or the corresponding amount of olive oil for 8 weeks. The indicators of liver function, glucose and lipid metabolism, and liver histology were compared among the different groups.
Hepatocyte-specific HIF-2α knockout had no effect on the growth, liver function, glucose or lipid metabolism in mice. CCl-treated KO and WT mice had a similar pattern of injury and inflammatory cell infiltration in the liver. Quantification of Masson staining, α-smooth muscle actin (α-SMA) immunohistochemistry, and the hydroxyproline (HYP) content revealed similar liver fibrosis levels between KO and WT mice injected intraperitoneally with CCl. Immunohistochemistry analysis suggested that HIF-2α was mainly expressed in the portal area and hepatic sinusoids but not in hepatocytes. Bioinformatics analyses further indicated that HIF-2α expression was neither liver specific nor hepatocyte specific, and the effect of HIF-2α in hepatocytes on liver fibrosis may not be as important as that in liver sinuses.
Hepatocyte HIF-2α expression may not be a key factor in the initiation of liver fibrogenesis, and hepatocyte-specific deletion of HIF-2α may not be the ideal therapeutic strategy for liver fibrosis.
缺氧诱导因子-2α（HIF-2α）缺乏对四氯化碳（CCl）诱导的肝纤维化模型的影响尚未得到证实。我们旨在研究肝实质细胞特异性 HIF-2α 缺失是否能改善小鼠 CCl 诱导的肝纤维化。
利用白蛋白启动子驱动 Cre 重组酶构建肝实质细胞特异性 HIF-2α 敲除小鼠。HIF-2α 敲除（KO）小鼠和 floxed 对照野生型（WT）小鼠分别给予正常饮食（ND），并每周接受两次腹腔注射 CCl 溶液（CCl 溶解于橄榄油）或相应量的橄榄油，共 8 周。比较各组小鼠的肝功能、糖脂代谢及肝组织学指标。
肝实质细胞特异性 HIF-2α 缺失对小鼠的生长、肝功能、糖脂代谢无影响。CCl 处理的 KO 和 WT 小鼠肝脏损伤和炎症细胞浸润模式相似。Masson 染色、α-平滑肌肌动蛋白（α-SMA）免疫组化和羟脯氨酸（HYP）含量定量分析显示，腹腔注射 CCl 的 KO 和 WT 小鼠肝纤维化程度相似。免疫组化分析表明，HIF-2α 主要表达于门脉区和肝窦，而不表达于肝细胞。生物信息学分析进一步表明，HIF-2α 的表达既非肝脏特异性，也非肝细胞特异性，HIF-2α 在肝细胞中对肝纤维化的作用可能不如在肝窦中重要。
肝实质细胞 HIF-2α 表达可能不是肝纤维化发生的关键因素，肝实质细胞特异性 HIF-2α 缺失可能不是肝纤维化的理想治疗策略。
