The liver copper status alters the development of steatosis in mice

Background The association between copper (Cu) misbalance and liver steatosis has been reported in experimental models and in human disease. Inactivation of the copper transporter ATP7B causes copper (Cu) accumulation in the liver and Wilson Disease (WD). The contribution of Cu misbalance to the development of liver steatosis is not well understood.

Aim To address this issue, we compared the effect of a high- fat- high- sugar diet (HFHSD) on C57BL/6J (wt) and C57BL/6J Atp7b-/-knockout mice (WD model).

Methods C57BL/6J (wt) and C57BL/6J Atp7b-/- mice were fed HFHSD or normal chow (NC) for 12 weeks (starting at age of 4 weeks). At each time point, all animals were evaluated for their body fat content using NMR spectrometry, liver enzymes, lipid profile, copper levels (by atomic absorption spectrometry), and mitochondrial function (measuring Thioredoxin, NADP+/NADPH ratio, and cytochrome c activity). Proteomics analyzes of male livers were performed at the age of 16 weeks to compare affected pathways.

Results Atp7b^-/- mice accumulate less fat on HFHSD compared to the wt controls; the effect is more pronounced in males. Unexpectedly, the WD phenotype is less severe in Atp7b^-/- mice fed HFHSD compared to NC: liver enzymes are less elevated in Atp7b^-/- mice on HFHSD compared to NC, and lower than in wt mice on HFHSD. Cu levels are also lower in Atp7b^-/- mice fed HFHSD compared to NC. Proteomics analyzes reveal changes affecting the cholesterol and bile acid biosynthesis for the HFHSD groups. Atp7b^-/- mice fed the HFHSD show additional changes involving the cytochrome P450 system.

Conclusion Cu modifies the organism response to HFHSD in WD model and steatosis development through specific pathways. Reciprocally, HFHSD improves the WD liver phenotype by decreasing Cu levels. The results suggest tight metabolic connections between Cu homeostasis and steatosis development in a WD mouse model.

Publication History

Article published online:
08 September 2020