Metabolic Dysfunction-Associated Steatotic Liver Disease in Patients and Mice with Wilson Disease

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.