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2017 ; 66
(2
): 449-465
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Characterization of ferroptosis in murine models of hemochromatosis
#MMPMID28195347
Wang H
; An P
; Xie E
; Wu Q
; Fang X
; Gao H
; Zhang Z
; Li Y
; Wang X
; Zhang J
; Li G
; Yang L
; Liu W
; Min J
; Wang F
Hepatology
2017[Aug]; 66
(2
): 449-465
PMID28195347
show ga
Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell
death implicated in brain, kidney, and heart pathology. However, the biological
roles of iron and iron metabolism in ferroptosis remain poorly understood. Here,
we studied the functional role of iron and iron metabolism in the pathogenesis of
ferroptosis. We found that ferric citrate potently induces ferroptosis in murine
primary hepatocytes and bone marrow-derived macrophages. Next, we screened for
ferroptosis in mice fed a high-iron diet and in mouse models of hereditary
hemochromatosis with iron overload. We found that ferroptosis occurred in mice
fed a high-iron diet and in two knockout mouse lines that develop severe iron
overload (Hjv(-/-) and Smad4(Alb/Alb) mice) but not in a third line that develops
only mild iron overload (Hfe(-/-) mice). Moreover, we found that iron
overload-induced liver damage was rescued by the ferroptosis inhibitor
ferrostatin-1. To identify the genes involved in iron-induced ferroptosis, we
performed microarray analyses of iron-treated bone marrow-derived macrophages.
Interestingly, solute carrier family 7, member 11 (Slc7a11), a known
ferroptosis-related gene, was significantly up-regulated in iron-treated cells
compared with untreated cells. However, genetically deleting Slc7a11 expression
was not sufficient to induce ferroptosis in mice. Next, we studied iron-treated
hepatocytes and bone marrow-derived macrophages isolated from Slc7a11(-/-) mice
fed a high-iron diet. CONCLUSION: We found that iron treatment induced
ferroptosis in Slc7a11(-/-) cells, indicating that deleting Slc7a11 facilitates
the onset of ferroptosis specifically under high-iron conditions; these results
provide compelling evidence that iron plays a key role in triggering
Slc7a11-mediated ferroptosis and suggest that ferroptosis may be a promising
target for treating hemochromatosis-related tissue damage. (Hepatology
2017;66:449-465).
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