PMID- 34774873
OWN - NLM
STAT- MEDLINE
DCOM- 20211214
LR  - 20211214
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 287
DP  - 2021 Dec 15
TI  - GPR40 agonist inhibits NLRP3 inflammasome activation via modulation of nuclear 
      factor-kappaB and sarco/endoplasmic reticulum Ca(2+)-ATPase.
PG  - 120127
LID - S0024-3205(21)01114-0 [pii]
LID - 10.1016/j.lfs.2021.120127 [doi]
AB  - The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a 
      multi-protein intracellular complex that activates proinflammatory cytokines, 
      including interleukin (IL)-1beta and IL-18. Inflammasome activation is related to 
      metabolic inflammation, such as the progression of non-alcoholic steatohepatitis. 
      Fasiglifam (TAK875), a selective G-protein coupled receptor 40 (GPR40) agonist 
      with high affinity, significantly improves glucose-dependent insulin secretion 
      and weight gain without hypoglycemia. Interestingly, we found that two GPR40 
      agonists, TAK875 and AMG1638, suppressed activation of the NLRP3 inflammasome in 
      bone marrow-derived macrophages (BMDMs). TAK875 inhibited inflammasome activation 
      by blocking formation of apoptosis-associated speck-like protein containing a 
      CARD (ASC), an inflammasome component. TAK875 also suppressed NLRP3 
      inflammasome-induced pyroptosis of BMDMs. Moreover, nuclear factor-kappa B 
      (NF-kappaB)-dependent priming of the NLRP3 inflammasome was partially inhibited by 
      TAK875 and AMG1638. The intracellular Ca(2+) increase caused by ATP, nigericin 
      (pore-forming toxin), or endoplasmic reticulum stress activates the NLRP3 
      inflammasome. Pre-exposure of BMDMs to TAK875 suppressed the ATP-induced 
      intracellular Ca(2+) increase, which was reversed by thapsigargin, a 
      sarco/endoplasmic reticulum Ca(2+)-ATPase inhibitor. Oral administration of mice 
      with TAK875 suppressed the increase in serum IL-1beta in mice treated with 
      lipopolysaccharide/D-galactosamine in vivo. These findings indicate that the free 
      fatty acid-sensing GPR40 plays a key role in the NLRP3 inflammasome pathway.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Park, Jeongwoo
AU  - Park J
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea.
FAU - Lee, Moo-Yeol
AU  - Lee MY
AD  - College of Pharmacy, Dongguk University, Goyang-si, Gyeonggi-do 10326, Republic 
      of Korea.
FAU - Seo, Yoon-Seok
AU  - Seo YS
AD  - College of Pharmacy, Dongguk University, Goyang-si, Gyeonggi-do 10326, Republic 
      of Korea.
FAU - Kang, ByeongSeok
AU  - Kang B
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea.
FAU - Lim, Sung-Chul
AU  - Lim SC
AD  - Department of Pathology, College of Medicine, Chosun University, Gwangju 61452, 
      Republic of Korea.
FAU - Kang, Keon Wook
AU  - Kang KW
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea. Electronic address: 
      kwkang@snu.ac.kr.
LA  - eng
PT  - Journal Article
DEP - 20211111
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Benzofurans)
RN  - 0 (Ffar1 protein, mouse)
RN  - 0 (NF-kappa B)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Sulfones)
RN  - 0 (TAK-875)
RN  - EC 7.2.2.10 (Calcium-Transporting ATPases)
SB  - IM
MH  - Animals
MH  - Benzofurans/pharmacology
MH  - Calcium-Transporting ATPases/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Endoplasmic Reticulum/drug effects/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/antagonists & inhibitors/*metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & 
      inhibitors/*metabolism
MH  - RAW 264.7 Cells
MH  - Receptors, G-Protein-Coupled/*agonists/*metabolism
MH  - Sulfones/pharmacology
OTO - NOTNLM
OT  - GPR40
OT  - Inflammasome
OT  - NLRP3
OT  - SERCA
OT  - TAK875
OT  - TAK875 (Falsiglifam PubChem CID: 24857286)
EDAT- 2021/11/15 06:00
MHDA- 2021/12/15 06:00
CRDT- 2021/11/14 20:50
PHST- 2021/08/06 00:00 [received]
PHST- 2021/11/02 00:00 [revised]
PHST- 2021/11/04 00:00 [accepted]
PHST- 2021/11/15 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/11/14 20:50 [entrez]
AID - S0024-3205(21)01114-0 [pii]
AID - 10.1016/j.lfs.2021.120127 [doi]
PST - ppublish
SO  - Life Sci. 2021 Dec 15;287:120127. doi: 10.1016/j.lfs.2021.120127. Epub 2021 Nov 
      11.