Chen Hui, Zhao Wenshan, Yan Xuzhen, Huang Tao, Yang Aiting
Digestive Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
J Clin Transl Hepatol. 2022 Aug 28;10(4):577-588. doi: 10.14218/JCTH.2021.00289. Epub 2022 Jan 4.
Iron overload can contribute to the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Hepcidin (Hamp), which is primarily synthesized in hepatocytes, is a key regulator of iron metabolism. However, the role of Hamp in NASH remains unclear. Therefore, we aimed to elucidate the role of Hamp in the pathophysiology of NASH.
Male mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for 16 weeks to establish the mouse NASH model. A choline-supplemented amino acid-defined (CSAA) diet was used as the control diet. Recombinant adeno-associated virus genome 2 serotype 8 vector expressing Hamp (rAAV2/8-Hamp) or its negative control (rAAV2/8-NC) was administered intravenously at week 8 of either the CDAA or CSAA diet.
rAAV2/8-Hamp treatment markedly decreased liver weight and improved hepatic steatosis in the CDAA-fed mice, accompanied by changes in lipogenesis-related genes and adiponectin expression. Compared with the control group, rAAV2/8-Hamp therapy attenuated liver damage, with mice exhibiting reduced histological NAFLD inflammation and fibrosis, as well as lower levels of liver enzymes. Moreover, α-smooth muscle actin-positive activated hepatic stellate cells (HSCs) and CD68-postive macrophages increased in number in the CDAA-fed mice, which was reversed by rAAV2/8-Hamp treatment. Consistent with the findings, overexpression of Hamp increased adiponectin expression in hepatocytes and Hamp treatment inhibited HSC activation.
Overexpression of Hamp using rAAV2/8-Hamp robustly attenuated liver steatohepatitis, inflammation, and fibrosis in an animal model of NASH, suggesting a potential therapeutic role for Hamp.
铁过载会促使非酒精性脂肪性肝病（NAFLD）进展为非酒精性脂肪性肝炎（NASH）。主要在肝细胞中合成的铁调素（Hamp）是铁代谢的关键调节因子。然而，Hamp在NASH中的作用仍不清楚。因此，我们旨在阐明Hamp在NASH病理生理学中的作用。
雄性小鼠喂食胆碱缺乏的L-氨基酸限定（CDAA）饮食16周以建立小鼠NASH模型。使用补充胆碱的氨基酸限定（CSAA）饮食作为对照饮食。在CDAA或CSAA饮食的第8周静脉注射表达Hamp的重组腺相关病毒基因组2血清型8载体（rAAV2/8-Hamp）或其阴性对照（rAAV2/8-NC）。
rAAV2/8-Hamp治疗显著降低了喂食CDAA小鼠的肝脏重量并改善了肝脂肪变性，同时伴有脂肪生成相关基因和脂联素表达的变化。与对照组相比，rAAV2/8-Hamp治疗减轻了肝脏损伤，小鼠的组织学NAFLD炎症和纤维化减轻，肝酶水平也降低。此外，喂食CDAA的小鼠中α-平滑肌肌动蛋白阳性的活化肝星状细胞（HSCs）和CD68阳性巨噬细胞数量增加，而rAAV2/8-Hamp治疗可使其逆转。与这些结果一致，Hamp的过表达增加了肝细胞中脂联素的表达，并且Hamp治疗抑制了HSC活化。
使用rAAV2/8-Hamp过表达Hamp可在NASH动物模型中显著减轻肝脏脂肪性肝炎、炎症和纤维化，提示Hamp具有潜在的治疗作用。
