Steatosis development in the mouse model of Wilson disease coincides with a muted inflammatory response

Background and aims Wilson disease (WnD) is caused by inactivation of the copper (Cu) transporter ATP7B and Cu accumulation in tissues. WnD manifestations vary significantly, and modifying factors are not fully understood. Liver steatosis is often, but not always, observed in WnD. To identify factors influencing the development of steatosis in WnD, we compared mice with a diet-induced steatosis and Atp7b^-/- mice with and without high calorie supplementation in the diet.

Methods Control C57BL/6J and C57BL/6J Atp7b^-/- mice were fed Western diet or normal chow for 6 and 12 weeks. Serum, liver metabolites, and hepatic Cu were measured. Liver status was evaluated by histology and transaminase analyses. The body fat content was determined by NMR. Liver proteomes were compared using quantitative mass-spectrometry.

Results Western diet, overall, affected Atp7b^-/- males and females similarly. The diet increased the animals body fat content and induced steatosis without changing the weight gain. Although hepatic Cu remained elevated, liver inflammation was reduced. The diet diminished the integrin, IL6/IL8, and MAPK signaling, reversed changes in cell cycle machinery and cytoskeleton, and normalized several serum metabolites. The wildtype and Atp7b^-/- livers showed striking similarities in their responses to Western diet, including down-regulation of cholesterol biosynthesis, altered LXR/RXR signaling, and changes in cytoskeleton.

Conclusions In Atp7b^-/- mice, calorie supplementation modifies liver phenotype by decreasing inflammation, while promoting steatosis. Similar changes of cellular pathways during steatosis development in wild-type and Atp7b^-/- mice explain histologic overlap between WnD and non-alcoholic fatty liver disease despite opposite Cu changes in these disorders.

 

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Publication History

Article published online:
07 September 2021