TY - JOUR
T1 - Oxysterol misbalance critically contributes to Wilson disease pathogenesis
AU - Dev, Som
AU - Muchenditsi, Abigael
AU - Gottlieb, Aline
AU - Deme, Pragney
AU - Murphy, Sean
AU - Gabrielson, Kathleen L.
AU - Dong, Yixuan
AU - Hughes, Robert
AU - Haughey, Norman J.
AU - Hamilton, James P.
AU - Lutsenko, Svetlana
N1 - Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved.
PY - 2022/10/21
Y1 - 2022/10/21
N2 - Wilson disease (WD) is a metabolic disorder caused by inactivation of the copper-transporting ATPase 2 (ATP7B) and copper (Cu) overload in tissues. Excess Cu causes oxidative stress and pathologic changes with poorly understood mechanistic connections. In Atp7b−/− mice with established liver disease, Cu overload activates the stress-sensitive transcription factor Nrf2 (nuclear factor erythroid-derived 2-like 2). Nrf2 targets, especially sulfotransferase 1e1 (Sult1e1), are strongly induced and cause elevation of sulfated sterols, whereas oxysterols are decreased. This sterol misbalance results in inhibition of the liver X receptor (LXR) and up-regulation of LXR targets associated with inflammatory responses. Pharmacological inhibition of Sult1e1 partially reverses oxysterol misbalance and LXR inhibition. Contribution of this pathway to advanced hepatic WD was demonstrated by treating mice with an LXR agonist. Treatment decreased inflammation by reducing expression of proinflammatory molecules, diminished fibrosis by down-regulating the noncanonical transforming growth factor–β signaling pathway, and improved liver morphology and function. Thus, the identified pathway is an important driver of WD.
AB - Wilson disease (WD) is a metabolic disorder caused by inactivation of the copper-transporting ATPase 2 (ATP7B) and copper (Cu) overload in tissues. Excess Cu causes oxidative stress and pathologic changes with poorly understood mechanistic connections. In Atp7b−/− mice with established liver disease, Cu overload activates the stress-sensitive transcription factor Nrf2 (nuclear factor erythroid-derived 2-like 2). Nrf2 targets, especially sulfotransferase 1e1 (Sult1e1), are strongly induced and cause elevation of sulfated sterols, whereas oxysterols are decreased. This sterol misbalance results in inhibition of the liver X receptor (LXR) and up-regulation of LXR targets associated with inflammatory responses. Pharmacological inhibition of Sult1e1 partially reverses oxysterol misbalance and LXR inhibition. Contribution of this pathway to advanced hepatic WD was demonstrated by treating mice with an LXR agonist. Treatment decreased inflammation by reducing expression of proinflammatory molecules, diminished fibrosis by down-regulating the noncanonical transforming growth factor–β signaling pathway, and improved liver morphology and function. Thus, the identified pathway is an important driver of WD.
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U2 - 10.1126/sciadv.adc9022
DO - 10.1126/sciadv.adc9022
M3 - Article
C2 - 36260680
AN - SCOPUS:85140283109
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 42
M1 - eadc9022
ER -