TY - JOUR
T1 - Hepatic Steatosis in the Mouse Model of Wilson Disease Coincides with a Muted Inflammatory Response
AU - Gottlieb, Aline
AU - Dev, Som
AU - DeVine, Lauren
AU - Gabrielson, Kathleen L.
AU - Cole, Robert N.
AU - Hamilton, James P.
AU - Lutsenko, Svetlana
N1 - Publisher Copyright:
© 2022 American Society for Investigative Pathology
PY - 2022/1
Y1 - 2022/1
N2 - Wilson disease (WND) is caused by inactivation of the copper transporter ATP7B and copper accumulation in tissues. WND presentations vary from liver steatosis to inflammation, fibrosis, and liver failure. Diets influence the liver phenotype in WND, but findings are inconsistent. To better understand the impact of excess calories on liver phenotype in WND, the study compared C57BL/6J Atp7b−/− and C57BL/6J mice fed for 12 weeks with Western diet or normal chow. Serum and liver metabolites, body fat content, liver histology, hepatic proteome, and copper content were analyzed. Wild-type and Atp7b−/− livers showed striking similarities in their responses to Western diet, most notably down-regulation of cholesterol biosynthesis, altered nuclear receptor signaling, and changes in cytoskeleton. Western diet increased body fat content and induced liver steatosis in males and females regardless of genotype; however, the effects were less pronounced in Atp7b−/− mice compared with those in the wild type mice. Although hepatic copper remained elevated in Atp7b−/− mice, liver inflammation was reduced. The diet diminished signaling by Rho GTPases, integrin, IL8, and reversed changes in cell cycle machinery and cytoskeleton. Overall, high calories decreased inflammatory response in favor of steatosis without improving markers of cell viability. 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 copper changes in these disorders.
AB - Wilson disease (WND) is caused by inactivation of the copper transporter ATP7B and copper accumulation in tissues. WND presentations vary from liver steatosis to inflammation, fibrosis, and liver failure. Diets influence the liver phenotype in WND, but findings are inconsistent. To better understand the impact of excess calories on liver phenotype in WND, the study compared C57BL/6J Atp7b−/− and C57BL/6J mice fed for 12 weeks with Western diet or normal chow. Serum and liver metabolites, body fat content, liver histology, hepatic proteome, and copper content were analyzed. Wild-type and Atp7b−/− livers showed striking similarities in their responses to Western diet, most notably down-regulation of cholesterol biosynthesis, altered nuclear receptor signaling, and changes in cytoskeleton. Western diet increased body fat content and induced liver steatosis in males and females regardless of genotype; however, the effects were less pronounced in Atp7b−/− mice compared with those in the wild type mice. Although hepatic copper remained elevated in Atp7b−/− mice, liver inflammation was reduced. The diet diminished signaling by Rho GTPases, integrin, IL8, and reversed changes in cell cycle machinery and cytoskeleton. Overall, high calories decreased inflammatory response in favor of steatosis without improving markers of cell viability. 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 copper changes in these disorders.
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U2 - 10.1016/j.ajpath.2021.09.010
DO - 10.1016/j.ajpath.2021.09.010
M3 - Article
C2 - 34627751
AN - SCOPUS:85121219453
SN - 0002-9440
VL - 192
SP - 146
EP - 159
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -