Overexpression of Hepcidin Alleviates Steatohepatitis and Fibrosis in a Diet-induced Nonalcoholic Steatohepatitis.
Overexpression of Hepcidin Alleviates Steatohepatitis and Fibrosis in a Diet-induced Nonalcoholic Steatohepatitis.
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铁调素的过度表达可减轻饮食引起的非酒精性脂肪性肝炎中的脂肪性肝炎和纤维化
DOI：
10.14218/jcth.2021.00289
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发表时间：
2022-08-28
影响因子：
3.6
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中科院分区：
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铁超载可导致非酒精性脂肪肝病 (NAFLD) 进展为非酒精性脂肪性肝炎 (NASH)。铁调素 (Hamp) 主要在肝细胞中合成，是铁代谢的关键调节剂。然而，Hamp 在 NASH 中的作用仍不清楚。因此，我们的目的是阐明 Hamp 在 NASH 病理生理学中的作用。雄性小鼠饲喂缺乏胆碱的L-氨基酸（CDAA）饮食16周，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，静脉内施用表达 Hamp (rAAV2/8-Hamp) 的重组腺相关病毒基因组 2 血清型 8 载体或其阴性对照 (rAAV2/8-NC)。 rAAV2/8-Hamp 治疗显着降低了 CDAA 喂养小鼠的肝脏重量并改善了肝脏脂肪变性，同时伴随着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 疗法减轻了肝损伤，小鼠的组织学 NAFLD 炎症和纤维化减少，肝酶水平降低。此外，在喂食 CDAA 的小鼠中，α-平滑肌肌动蛋白阳性激活的肝星状细胞 (HSC) 和 CD68 阳性巨噬细胞数量增加，而 rAAV2/8-Hamp 治疗可逆转这一现象。与体内研究结果一致，Hamp 的过度表达增加了肝细胞中脂联素的表达，并且 Hamp 处理抑制了 HSC 活化。在 NASH 动物模型中，使用 rAAV2/8-Hamp 过度表达 Hamp 可以显着减轻肝脏脂肪性肝炎、炎症和纤维化，这表明 Hamp 具有潜在的治疗作用。
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 in vivo 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.