PMID- 38540237
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240330
IS  - 2227-9059 (Print)
IS  - 2227-9059 (Electronic)
IS  - 2227-9059 (Linking)
VI  - 12
IP  - 3
DP  - 2024 Mar 11
TI  - Different Coactivator Recruitment to Human PPARalpha/delta/gamma Ligand-Binding Domains by 
      Eight PPAR Agonists to Treat Nonalcoholic Fatty Liver Disease.
LID - 10.3390/biomedicines12030624 [doi]
LID - 624
AB  - Three peroxisome proliferator-activated receptor subtypes, PPARalpha, PPAR(ss/)delta, and 
      PPARgamma, exert ligand-dependent transcriptional control in concert with retinoid X 
      receptors (RXRs) on various gene sets harboring PPAR response elements (PPREs) in 
      their promoter regions. Ligand-bound PPAR/RXR complexes do not directly regulate 
      transcription; instead, they recruit multiprotein coactivator complexes to 
      specific genomic regulatory loci to cooperatively activate gene transcription. 
      Several coactivators are expressed in a single cell; however, a ligand-bound PPAR 
      can be associated with only one coactivator through a consensus LXXLL motif. 
      Therefore, altered gene transcription induced by PPAR subtypes/agonists may be 
      attributed to the recruitment of various coactivator species. Using a 
      time-resolved fluorescence resonance energy transfer assay, we analyzed the 
      recruitment of four coactivator peptides (PGC1alpha, CBP, SRC1, and TRAP220) to human 
      PPARalpha/delta/gamma-ligand-binding domains (LBDs) using eight PPAR dual/pan agonists 
      (bezafibrate, fenofibric acid, pemafibrate, pioglitazone, elafibranor, 
      lanifibranor, saroglitazar, and seladelpar) that are/were anticipated to treat 
      nonalcoholic fatty liver disease. These agonists all recruited four coactivators 
      to PPARalpha/gamma-LBD with varying potencies and efficacy. Only five agonists 
      (bezafibrate, pemafibrate, elafibranor, lanifibranor, and seladelpar) recruited 
      all four coactivators to PPARdelta-LBD, and their concentration-dependent responses 
      differed from those of PPARalpha/gamma-LBD. These results indicate that altered gene 
      expression through consensus PPREs by different PPAR subtypes/agonists may be 
      caused, in part, by different coactivators, which may be responsible for the 
      unique pharmacological properties of these PPAR agonists.
FAU - Kamata, Shotaro
AU  - Kamata S
AUID- ORCID: 0000-0002-2400-6533
AD  - Department of Health Chemistry, Showa Pharmaceutical University, Machida 
      194-8543, Tokyo, Japan.
FAU - Honda, Akihiro
AU  - Honda A
AD  - Department of Health Chemistry, Showa Pharmaceutical University, Machida 
      194-8543, Tokyo, Japan.
FAU - Kashiwagi, Nonoka
AU  - Kashiwagi N
AD  - Department of Health Chemistry, Showa Pharmaceutical University, Machida 
      194-8543, Tokyo, Japan.
FAU - Shimamura, Ayumi
AU  - Shimamura A
AD  - Department of Health Chemistry, Showa Pharmaceutical University, Machida 
      194-8543, Tokyo, Japan.
FAU - Yashiro, Sayaka
AU  - Yashiro S
AD  - Department of Health Chemistry, Showa Pharmaceutical University, Machida 
      194-8543, Tokyo, Japan.
FAU - Komori, Yuna
AU  - Komori Y
AD  - Department of Health Chemistry, Showa Pharmaceutical University, Machida 
      194-8543, Tokyo, Japan.
FAU - Hosoda, Aoi
AU  - Hosoda A
AD  - Department of Health Chemistry, Showa Pharmaceutical University, Machida 
      194-8543, Tokyo, Japan.
FAU - Akahoshi, Noriyuki
AU  - Akahoshi N
AD  - Department of Health Chemistry, Showa Pharmaceutical University, Machida 
      194-8543, Tokyo, Japan.
FAU - Ishii, Isao
AU  - Ishii I
AUID- ORCID: 0000-0002-5367-205X
AD  - Department of Health Chemistry, Showa Pharmaceutical University, Machida 
      194-8543, Tokyo, Japan.
LA  - eng
GR  - 22K15049/Ministry of Education, Culture, Sports, Science and Technology/
GR  - 22H05577/Japan Society for the Promotion of Science/
PT  - Journal Article
DEP - 20240311
PL  - Switzerland
TA  - Biomedicines
JT  - Biomedicines
JID - 101691304
PMC - PMC10967972
OTO - NOTNLM
OT  - PPAR response element
OT  - PPARgamma coactivator-1alpha
OT  - coactivator
OT  - dual/pan agonist
OT  - gene expression
OT  - nonalcoholic fatty liver disease
OT  - nuclear receptor
OT  - peroxisome proliferator-activated receptor
OT  - time-resolved fluorescence resonance energy transfer
OT  - transcription factor
COIS- The authors declare no conflicts of interest.
EDAT- 2024/03/28 06:45
MHDA- 2024/03/28 06:46
PMCR- 2024/03/11
CRDT- 2024/03/28 01:06
PHST- 2024/02/13 00:00 [received]
PHST- 2024/03/02 00:00 [revised]
PHST- 2024/03/08 00:00 [accepted]
PHST- 2024/03/28 06:46 [medline]
PHST- 2024/03/28 06:45 [pubmed]
PHST- 2024/03/28 01:06 [entrez]
PHST- 2024/03/11 00:00 [pmc-release]
AID - biomedicines12030624 [pii]
AID - biomedicines-12-00624 [pii]
AID - 10.3390/biomedicines12030624 [doi]
PST - epublish
SO  - Biomedicines. 2024 Mar 11;12(3):624. doi: 10.3390/biomedicines12030624.