In Wilson disease (WD), fatty liver was linked to cardiometabolic risk, and in ATP7B-knockout mice, a high-fat diet – not copper overload – drove steatohepatitis and fibrosis, according to a recent study.
Researchers examined hepatic steatosis in WD in a retrospective cohort and in a mouse model focusing on diet and metabolic risk. Among 61 hospitalized adults with WD, 12 percent had imaging or histologic steatosis. All patients with steatosis had at least one cardiometabolic risk factor, and body mass index was higher compared with patients without steatosis (26 ± 2.0 kg/m² versus 23 ± 0.6 kg/m²; P = 0.039). Copper measures and liver enzymes did not differ meaningfully by steatosis status. In an age- and sex-matched comparison with 122 patients with metabolic dysfunction–associated steatotic liver disease, the metabolic dysfunction group had higher blood pressure, body mass index, fasting glucose, hemoglobin A1c, Homeostasis Model Assessment of Insulin Resistance scores, triglycerides, low-density lipoprotein, and alanine aminotransferase, whereas the WD group had higher alkaline phosphatase and total bilirubin and lower albumin.
Using CRISPR/Cas9, the study, publihsed in The American Journal of Pathology, generated ATP7B knockout (KO) mice. On chow through 40 weeks, KO mice showed hepatic copper accumulation, increased 24-hour urinary copper, and reduced plasma ceruloplasmin activity without spontaneous liver injury or neurologic deficits. Under physiological conditions, KO mice had lower plasma and hepatic triglyceride and cholesterol versus wild type; liver-directed adeno-associated viral ATP7B expression partially increased lipid measures.
With 24 weeks of high-fat diet (HFD), steatohepatitis occurred in both genotypes. KO mice had higher steatosis scores, higher hepatic triglyceride and plasma cholesterol, and higher aspartate aminotransferase versus wild type. Masson staining and α–smooth muscle actin immunohistochemistry showed more fibrosis in KO mice. Hepatic transcripts related to inflammation and fibrogenesis were increased. Transcriptomic analyses in KO livers on HFD showed enrichment of extracellular matrix organization, angiogenesis, apoptosis, and inflammatory pathways. In KO mice, HFD was associated with lower hepatic copper and higher plasma copper and ceruloplasmin activity; similar directions were observed in wild type without statistical significance. The study noted that these shifts involve components of the Leipzig scoring system used for WD assessment.
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