PMID- 37915121
OWN - NLM
STAT- MEDLINE
DCOM- 20240108
LR  - 20240108
IS  - 2093-5978 (Electronic)
IS  - 2093-596X (Print)
IS  - 2093-596X (Linking)
VI  - 38
IP  - 6
DP  - 2023 Dec
TI  - AM1638, a GPR40-Full Agonist, Inhibited Palmitate- Induced ROS Production and 
      Endoplasmic Reticulum Stress, Enhancing HUVEC Viability in an NRF2-Dependent 
      Manner.
PG  - 760-769
LID - 10.3803/EnM.2023.1774 [doi]
AB  - BACKGRUOUND: G protein-coupled receptor 40 (GPR40) is a key molecule in diabetes 
      and fatty liver, but its role in endothelial dysfunction remains unclear. Our 
      objective in this study was to determine whether GPR40 agonists protect 
      endothelial cells against palmitatemediated oxidative stress. METHODS: Human 
      umbilical vein endothelial cells (HUVECs) were used to investigate effects of 
      various GPR40 agonists on vascular endothelium. RESULTS: In HUVECs, AM1638, a 
      GPR40-full agonist, enhanced nuclear factor erythroid 2-related factor 2 (NRF2) 
      translocation to the nucleus and heme oxygenase-1 (HO-1) expression, which 
      blocked palmitate-induced superoxide production. Those antioxidant effects were 
      not detected after treatment with LY2922470 or TAK875, GPR40-partial agonists, 
      suggesting that GPR40 regulates reactive oxygen species (ROS) removal in a 
      ligand-dependent manner. We also found that palmitate-induced 
      CCAAT/enhancer-binding protein homologous protein expression; X-box binding 
      protein-1 splicing, nuclear condensation, and fragmentation; and caspase-3 
      cleavage were all blocked in an NRF2-dependent manner after AM1638 treatment. 
      Both LY2922470 and TAK875 also improved cell viability independent of the 
      NRF2/ROS pathway by reducing palmitate-mediated endoplasmic reticulum stress and 
      nuclear damage. GPR40 agonists thus have beneficial effects against palmitate in 
      HUVECs. In particular, AM1638 reduced palmitate-induced superoxide production and 
      cytotoxicity in an NRF2/HO-1 dependent manner. CONCLUSION: GPR40 could be 
      developed as a good therapeutic target to prevent or treat cardiovascular 
      diseases such as atherosclerosis.
FAU - Hwang, Hwan-Jin
AU  - Hwang HJ
AD  - BK21 Graduate Program, Department of Biomedical Sciences, Korea University 
      College of Medicine, Seoul, Korea.
FAU - Kim, Joo Won
AU  - Kim JW
AD  - BK21 Graduate Program, Department of Biomedical Sciences, Korea University 
      College of Medicine, Seoul, Korea.
FAU - Yun, SukHwan
AU  - Yun S
AD  - BK21 Graduate Program, Department of Biomedical Sciences, Korea University 
      College of Medicine, Seoul, Korea.
FAU - Park, Min Jeong
AU  - Park MJ
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea 
      University College of Medicine, Seoul, Korea.
FAU - Song, Eyun
AU  - Song E
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea 
      University College of Medicine, Seoul, Korea.
FAU - Jang, Sooyeon
AU  - Jang S
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea 
      University College of Medicine, Seoul, Korea.
FAU - Jang, Ahreum
AU  - Jang A
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea 
      University College of Medicine, Seoul, Korea.
FAU - Choi, Kyung Mook
AU  - Choi KM
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea 
      University College of Medicine, Seoul, Korea.
FAU - Baik, Sei Hyun
AU  - Baik SH
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea 
      University College of Medicine, Seoul, Korea.
FAU - Yoo, Hye Jin
AU  - Yoo HJ
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea 
      University College of Medicine, Seoul, Korea.
LA  - eng
GR  - 2022R1I1A1A01067910/National Research Foundation of Korea/
GR  - 2021R1A2C2008792/National Research Foundation of Korea/
GR  - Ministry of Education/
GR  - Korean Endocrine Society/
PT  - Journal Article
DEP - 20231102
PL  - Korea (South)
TA  - Endocrinol Metab (Seoul)
JT  - Endocrinology and metabolism (Seoul, Korea)
JID - 101554139
RN  - 0 (LY2922470)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 11062-77-4 (Superoxides)
RN  - 0 
      (3-cyclopropyl-3-(3-((2-(5,5-dimethylcyclopent-1-en-1-yl)-2'-fluoro-5'-methoxy-(1,1'-biphenyl)-4-yl)methoxy)phenyl)propanoic 
      acid)
SB  - IM
MH  - Humans
MH  - Endoplasmic Reticulum Stress
MH  - Human Umbilical Vein Endothelial Cells
MH  - *NF-E2-Related Factor 2/metabolism/pharmacology
MH  - Reactive Oxygen Species/metabolism/pharmacology
MH  - Receptors, G-Protein-Coupled/metabolism
MH  - *Superoxides/metabolism/pharmacology
PMC - PMC10765001
OTO - NOTNLM
OT  - Cytotoxicity
OT  - Endoplasmic reticulum stress
OT  - GPR40 agonist
OT  - Human umbilical vein endothelial cell
OT  - NRF2
OT  - Palmitates
COIS- CONFLICTS OF INTEREST No potential conflict of interest relevant to this article 
      was reported.
EDAT- 2023/11/02 06:42
MHDA- 2024/01/03 09:42
PMCR- 2023/12/01
CRDT- 2023/11/02 01:03
PHST- 2023/07/04 00:00 [received]
PHST- 2023/09/13 00:00 [accepted]
PHST- 2024/01/03 09:42 [medline]
PHST- 2023/11/02 06:42 [pubmed]
PHST- 2023/11/02 01:03 [entrez]
PHST- 2023/12/01 00:00 [pmc-release]
AID - EnM.2023.1774 [pii]
AID - enm-2023-1774 [pii]
AID - 10.3803/EnM.2023.1774 [doi]
PST - ppublish
SO  - Endocrinol Metab (Seoul). 2023 Dec;38(6):760-769. doi: 10.3803/EnM.2023.1774. 
      Epub 2023 Nov 2.