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2017 ; 8
(23
): 37657-37672
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Inhibition of NLRP3 inflammasome by thioredoxin-interacting protein in mouse
Kupffer cells as a regulatory mechanism for non-alcoholic fatty liver disease
development
#MMPMID28499273
He K
; Zhu X
; Liu Y
; Miao C
; Wang T
; Li P
; Zhao L
; Chen Y
; Gong J
; Cai C
; Li J
; Li S
; Ruan XZ
; Gong J
Oncotarget
2017[Jun]; 8
(23
): 37657-37672
PMID28499273
show ga
NOD-like receptor (NLR) NLRP3 inflammasome activation has been implicated in the
progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty
liver (NAFL) to non-alcoholic steatohepatitis (NASH). It has been also shown that
palmitic acid (PA) activates NLRP3 inflammasome and promotes interleukin-1?
(IL-1?) secretion in Kupffer cells (KCs). However, the specific mechanism of the
NLRP3 inflammasome activation is unclear. We studies the molecular mechanisms by
investigating the roles of Thioredoxin-interacting protein (TXNIP) and NLRP3 on
NAFLD development in patients, high-fat diet (HFD)-induced NAFL and methionine
choline deficient (MCD) diet-induced NASH in wild type (WT), TXNIP-/-
(thioredoxin-interacting protein) and NLRP3-/- mice, and isolated KCs. We found
that the expressions of NLRP3 and TXNIP in human liver tissues were higher in
NASH group than in NAFL group. Furthermore, co-immunoprecipitation analyses show
that activation of the TXNIP-NLRP3 inflammasome protein complex occurred in KCs
of NASH WT mice rather than NAFL WT mice, thus suggesting that the formation and
activation of this protein complex is mainly involved in the development of NASH.
NLRP3-/- mice exhibited less severe NASH than WT mice in MCD diet model, whereas
TXNIP deficiency enhanced NLRP3 inflammasome activation and exacerbated liver
injury. PA triggered the activation and co-localization of the NLRP3 inflammasome
protein complex in KCs isolated from WT and TXNIP-/- but not NLRP3-/- mice, and
most of the complex co-localized with mitochondria of KCs following PA
stimulation. Taken together, our novel findings indicate that TXNIP plays a
protective and anti-inflammatory role in the development of NAFLD through binding
and suppressing NLRP3.