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Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote
insulin resistance in mice
#MMPMID24703845
Miao H
; Ou J
; Ma Y
; Guo F
; Yang Z
; Wiggins M
; Liu C
; Song W
; Han X
; Wang M
; Cao Q
; Chung BH
; Yang D
; Liang H
; Xue B
; Shi H
; Gan L
; Yu L
Cell Rep
2014[Apr]; 7
(1
): 223-35
PMID24703845
show ga
Overnutrition activates a proinflammatory program in macrophages to induce
insulin resistance (IR), but its molecular mechanisms remain incompletely
understood. Here, we show that saturated fatty acid and lipopolysaccharide, two
factors implicated in high-fat diet (HFD)-induced IR, suppress macrophage CGI-58
expression. Macrophage-specific CGI-58 knockout (MaKO) in mice aggravates
HFD-induced glucose intolerance and IR, which is associated with augmented
systemic/tissue inflammation and proinflammatory activation of adipose tissue
macrophages. CGI-58-deficient macrophages exhibit mitochondrial dysfunction due
to defective peroxisome proliferator-activated receptor (PPAR)? signaling.
Consequently, they overproduce reactive oxygen species (ROS) to potentiate
secretion of proinflammatory cytokines by activating NLRP3 inflammasome. Anti-ROS
treatment or NLRP3 silencing prevents CGI-58-deficient macrophages from
oversecreting proinflammatory cytokines and from inducing proinflammatory
signaling and IR in the cocultured fat slices. Anti-ROS treatment also prevents
exacerbation of inflammation and IR in HFD-fed MaKO mice. Our data thus establish
CGI-58 as a suppressor of overnutrition-induced NLRP3 inflammasome activation in
macrophages.
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