Cigarette Smoke Extract Modulates Functions of Peroxisome Proliferator-Activated Receptors

Cigarette smoke extract (CSE) contains many toxicants and may derange the physiological processes, such as cholesterol metabolism. We examined the impact of CSE on transcriptional regulation mediated peroxisome proliferator-activated receptors (PPARs) and its interaction with cofactors to elucidate...

Full description

Saved in:
Bibliographic Details
Published in:Biological & pharmaceutical bulletin 2019/10/01, Vol.42(10), pp.1628-1636
Main Authors: Matsushita, Midori, Futawaka, Kumi, Hayashi, Misa, Murakami, Kana, Mitsutani, Mana, Hatai, Mayuko, Watamoto, Yukiko, Yoshikawa, Noriko, Nakamura, Kazuki, Tagami, Tetsuya, Moriyama, Kenji
Format: Article
Language:eng ; jpn
Subjects:
Acrolein
Agonists
Amino Acid Substitution
Cell Line
Cholesterol
Cholesterol, LDL - metabolism
Cigarette smoke
co-factor
Cofactors
Gene regulation
GRIP1 protein
Humans
Isoforms
Lipid metabolism
Liver X receptors
Liver X Receptors - genetics
Low density lipoprotein
low density lipoprotein (LDL)-cholesterol
Metabolism
Molecular modelling
Nicotiana
Nuclear receptors
Peroxisome proliferator-activated receptors
Peroxisome Proliferator-Activated Receptors - genetics
Peroxisome Proliferator-Activated Receptors - metabolism
Pioglitazone
Protein Isoforms - genetics
Protein Isoforms - metabolism
Receptor density
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, LDL - genetics
signal transduction
Smoke
Toxicants
transcription
Transcription activation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cigarette smoke extract (CSE) contains many toxicants and may derange the physiological processes, such as cholesterol metabolism. We examined the impact of CSE on transcriptional regulation mediated peroxisome proliferator-activated receptors (PPARs) and its interaction with cofactors to elucidate differences in the molecular mechanism between CSE and other agonists of PPARs. We constructed several mutant PPARs (mPPARs) with amino acid substitution in the ligand-binding domain, which according to the molecular modeling, may affect the binding of agonists. In transient expression assays, each wild-type peroxisome proliferator-activated receptor (PPAR) mediated transcription stimulated by CSE was faintly yet significantly elevated compared to the control. The CSE-induced transcriptional activation was abolished in the H323A, H323Y, S342A, and H449A mPPARγs, although the activation elevated by pioglitazone was reserved. In the mPPARγ with Y473A and mPPARβ/δs with H286Y and Y436A, the pioglitazone-induced or L165041-activated transcriptional elevations were decreased and were lower than that of CSE-induced stimulation. These results suggested that CSE activated both mutant PPARs to be selectively different from those ligands. Mammalian two-hybrid assay illustrated that CSE could mildly recruit SRC1 or GRIP1 to the wild-type PPARγ. Representative ingredients, such as acrolein and crotonaldehyde present in CSE, could stimulate PPAR isoforms even at the toxicological concentrations and might possibly contribute to stimulatory effects. CSE mildly regulates the cholesterol metabolism-related genes, such as low density lipoprotein (LDL) receptor and Liver X receptor (LXR)β. In conclusion, these CSE effects the nuclear hormone receptors and their cofactors thereby disturbing metabolic phenomena. Therefore, CSE might be involved in cholesterol metabolism.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.b18-00991