PMID- 31694081
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200108
IS  - 2233-6079 (Print)
IS  - 2233-6087 (Electronic)
IS  - 2233-6079 (Linking)
VI  - 43
IP  - 5
DP  - 2019 Oct
TI  - PF-04620110, a Potent Antidiabetic Agent, Suppresses Fatty Acid-Induced NLRP3 
      Inflammasome Activation in Macrophages.
PG  - 683-699
LID - 10.4093/dmj.2019.0112 [doi]
AB  - BACKGROUND: Chronic inflammation has been linked to insulin resistance and type 2 
      diabetes mellitus (T2DM). High-fat diet (HFD)-derived fatty acid is associated 
      with the activation of chronic inflammation in T2DM. PF-04620110, which is 
      currently in phase 1 clinical trials as a selective acyl-CoA:diacylglycerol 
      acyltransferase-1 (DGAT1) inhibitor, is a potent anti-diabetic agent that may be 
      important for the regulation of chronic inflammation in T2DM. However, the 
      mechanisms by which PF-04620110 regulates fatty acid-induced chronic inflammation 
      remain unclear. METHODS: PF-04620110 was used in vitro and in vivo. 
      DGAT1-targeting gRNAs were used for deletion of mouse DGAT1 via CRISPR 
      ribonucleoprotein (RNP) system. The activation of NLRP3 inflammasome was measured 
      by immunoblot or cytokine analysis in vitro and in vivo. RESULTS: Here we show 
      that PF-04620110 suppressed fatty acid-induced nucleotide-binding domain, 
      leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) 
      inflammasome activation in macrophages. In contrast, PF-04620110 did not change 
      the activation of the NLR family, CARD-domain-containing 4 (NLRC4), or the absent 
      in melanoma 2 (AIM2) inflammasomes. Moreover, PF-04620110 inhibited K(+) efflux and 
      the NLRP3 inflammasome complex formation, which are required for NLRP3 
      inflammasome activation. PF-04620110 reduced the production of interleukin 1beta 
      (IL-1beta) and IL-18 and blood glucose levels in the plasma of mice fed HFD. 
      Furthermore, genetic inhibition of DGAT1 suppressed fatty acid-induced NLRP3 
      inflammasome activation. CONCLUSION: Our results suggest that PF-04620110 
      suppresses fatty acid-induced NLRP3 inflammasome activation.
CI  - Copyright (c) 2019 Korean Diabetes Association.
FAU - Jo, Seung Il
AU  - Jo SI
AUID- ORCID: 0000-0001-9638-5969
AD  - Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio 
      Science (SIMS), Soonchunhyang University, Cheonan, Korea.
FAU - Bae, Jung Hwan
AU  - Bae JH
AD  - Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio 
      Science (SIMS), Soonchunhyang University, Cheonan, Korea.
FAU - Kim, Seong Jin
AU  - Kim SJ
AD  - Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio 
      Science (SIMS), Soonchunhyang University, Cheonan, Korea.
FAU - Lee, Jong Min
AU  - Lee JM
AD  - Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio 
      Science (SIMS), Soonchunhyang University, Cheonan, Korea.
FAU - Jeong, Ji Hun
AU  - Jeong JH
AD  - Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio 
      Science (SIMS), Soonchunhyang University, Cheonan, Korea.
FAU - Moon, Jong Seok
AU  - Moon JS
AUID- ORCID: 0000-0002-2537-7854
AD  - Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-bio 
      Science (SIMS), Soonchunhyang University, Cheonan, Korea. jongseok81@sch.ac.kr.
LA  - eng
GR  - SCH/Soonchunhyang University/Korea
GR  - NRF-2019M3E5D1A02069071/NRF/National Research Foundation of Korea/Korea
PT  - Journal Article
PL  - Korea (South)
TA  - Diabetes Metab J
JT  - Diabetes & metabolism journal
JID - 101556588
PMC - PMC6834844
OTO - NOTNLM
OT  - Diabetes mellitus, type 2
OT  - Diacylglycerol O-acyltransferase
OT  - Fatty acids
OT  - Inflammasomes
OT  - NLR family, pyrin domain-containing 3 protein
OT  - PF-04620110
COIS- No potential conflict of interest relevant to this article was reported.
EDAT- 2019/11/07 06:00
MHDA- 2019/11/07 06:01
PMCR- 2019/10/01
CRDT- 2019/11/07 06:00
PHST- 2019/06/06 00:00 [received]
PHST- 2019/08/19 00:00 [accepted]
PHST- 2019/11/07 06:00 [entrez]
PHST- 2019/11/07 06:00 [pubmed]
PHST- 2019/11/07 06:01 [medline]
PHST- 2019/10/01 00:00 [pmc-release]
AID - 43.683 [pii]
AID - 10.4093/dmj.2019.0112 [doi]
PST - ppublish
SO  - Diabetes Metab J. 2019 Oct;43(5):683-699. doi: 10.4093/dmj.2019.0112.