Wang Zixuan, Xu Qingyang, Wang Mengyu, Xiao Qianqian, Xu Yanhuang, Wang Xiaoying, Shi Yiwen, Yang Ruixu, Fan Jian-Gao
Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Am J Pathol. 2025 Sep;195(9):1600-1618. doi: 10.1016/j.ajpath.2025.05.009. Epub 2025 Jun 9.
Wilson disease (WD) is a copper metabolism disorder caused by ATP7B gene mutations, and hepatic steatosis is not uncommon in WD. Therefore, the effects of ATP7B (ATPase copper-transporting beta) deficiency and/or a high-fat diet (HFD) on the development of steatohepatitis were investigated in mouse models and the relationship of hepatic steatosis with cardiometabolic factors was examined in patients with WD. A retrospective analysis of data was conducted on adults with WD. Of the 61 patients with WD, 11.5% had evidence of hepatic steatosis, significantly linked to cardiometabolic factors. Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) was used to generate Atp7b gene knockout (KO) mice, followed by a comprehensive phenotypic analysis. A HFD was administered to induce steatohepatitis, allowing for analysis of lipid metabolism and hepatic injuries in KO mice subjected to overnutrition. Although ATP7B KO mice under normal diet exhibited significant copper metabolism disorders without overt hepatic or neurologic injury, steatohepatitis was successfully induced in both wild-type and KO mice after 24 weeks of HFD. Compared with a normal diet, a HFD resulted in markedly decreased hepatic copper levels with obvious liver injury in KO mice. Moreover, HFD-fed KO mice exhibited significantly higher severity of hepatic steatosis, inflammation, and fibrosis than wild-type control mice. Results suggest that hepatic steatosis in WD relates more to acquired metabolic dysfunction than excess copper accumulation, underscoring the influence of nutritional excess on WD phenotypes.
威尔逊病（WD）是一种由ATP7B基因突变引起的铜代谢紊乱疾病，肝脂肪变性在WD中并不少见。因此，在小鼠模型中研究了ATP7B（ATP酶铜转运β）缺乏和/或高脂饮食（HFD）对脂肪性肝炎发展的影响，并在WD患者中检查了肝脂肪变性与心脏代谢因素的关系。对成年WD患者的数据进行了回顾性分析。在61例WD患者中，11.5%有肝脂肪变性的证据，这与心脏代谢因素显著相关。使用成簇规律间隔短回文重复序列/CRISPR相关蛋白9（CRISPR/Cas9）生成Atp7b基因敲除（KO）小鼠，随后进行全面的表型分析。给予HFD以诱导脂肪性肝炎，从而分析过度营养的KO小鼠的脂质代谢和肝损伤。尽管正常饮食下的ATP7B KO小鼠表现出明显的铜代谢紊乱，但无明显的肝或神经损伤，但在HFD喂养24周后，野生型和KO小鼠均成功诱导出脂肪性肝炎。与正常饮食相比，HFD导致KO小鼠肝铜水平明显降低，并伴有明显的肝损伤。此外，HFD喂养的KO小鼠的肝脂肪变性、炎症和纤维化严重程度明显高于野生型对照小鼠。结果表明，WD中的肝脂肪变性更多地与获得性代谢功能障碍有关，而不是过量的铜积累，这突出了营养过剩对WD表型的影响。
