Interleukin-1β decreases hepatic ATP-binding cassette subfamily A member 1 expression through p38 mitogen-activated protein kinase signaling and an H-89-sensitive pathway
Abstract
Steatotic liver disease is a common metabolic disorder, and interleukin-1β (IL-1β) contributes to hepatic inflammation and lipid accumulation. ATP-binding cassette subfamily A member 1 (ABCA1) regulates cholesterol efflux and lipid homeostasis. This study examined whether IL-1β suppresses hepatic ABCA1 expression and explored the underlying signaling and transcriptional mechanisms. Primary mouse hepatocytes and HepG2 cells were treated with IL-1β. ABCA1 expression was assessed by Western blotting and RT-qPCR, and ABCA1 promoter activity was examined using luciferase reporter assays with inhibitors targeting phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (p38 MAPK), or an H-89-sensitive pathway. Prolactin regulatory element-binding protein (PREB) involvement was evaluated by nuclear protein analysis, PREB-binding-site mutation, and siRNA-mediated knockdown. Lipid accumulation was assessed by intracellular cholesterol measurement and Oil Red O staining. IL-1β decreased ABCA1 protein and mRNA expression in a dose- and time-dependent manner and suppressed ABCA1 promoter activity. Inhibition of p38 MAPK or treatment with H-89 attenuated IL-1β-induced suppression of promoter activity and endogenous ABCA1 expression. Representative immunoblotting showed that IL-1β enhanced p38 MAPK phosphorylation, whereas SB203580 attenuated this response. IL-1β reduced nuclear PREB expression, and p38 MAPK inhibition restored nuclear PREB expression. Mutation of the PREB-binding site or PREB knockdown abolished IL-1β-mediated suppression of ABCA1 expression. IL-1β also increased intracellular cholesterol content and Oil Red O-positive lipid accumulation. These findings suggest that IL-1β suppresses hepatic ABCA1 expression through p38 MAPK signaling and an H-89-sensitive pathway, at least partly involving PREB-associated transcriptional regulation, and that this suppression is associated with hepatocellular lipid accumulation.
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BibTeX
@article{lyu2026interleukin1β,
title = {{Interleukin-1β decreases hepatic ATP-binding cassette subfamily A member 1 expression through p38 mitogen-activated protein kinase signaling and an H-89-sensitive pathway}},
author = {Jingya Lyu and Kensaku Fukunaga and Zhangchi He and Hitomi Imachi and Toshihiro Kobayashi and Takanobu Saheki and Takafumi Yoshimura and Eri Harada and Kosuke Izumi and Wenyi Jiang and Haotian Zhang and Ly Rathana and Hisakazu Iwama and Jinghui Guo and Koji Murao},
journal = {Endocrine Journal},
year = {2026},
month = aug,
doi = {10.1507/endocrj.ej26-0223},
url = {https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ26-0223/_article},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Interleukin-1β decreases hepatic ATP-binding cassette subfamily A member 1 expression through p38 mitogen-activated protein kinase signaling and an H-89-sensitive pathway
AU - Jingya Lyu
AU - Kensaku Fukunaga
AU - Zhangchi He
AU - Hitomi Imachi
AU - Toshihiro Kobayashi
AU - Takanobu Saheki
AU - Takafumi Yoshimura
AU - Eri Harada
AU - Kosuke Izumi
AU - Wenyi Jiang
AU - Haotian Zhang
AU - Ly Rathana
AU - Hisakazu Iwama
AU - Jinghui Guo
AU - Koji Murao
PY - 2026
DA - 2026/08/25
JO - Endocrine Journal
DO - 10.1507/endocrj.ej26-0223
UR - https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ26-0223/_article
AB - Steatotic liver disease is a common metabolic disorder, and interleukin-1β (IL-1β) contributes to hepatic inflammation and lipid accumulation. ATP-binding cassette subfamily A member 1 (ABCA1) regulates cholesterol efflux and lipid homeostasis. This study examined whether IL-1β suppresses hepatic ABCA1 expression and explored the underlying signaling and transcriptional mechanisms. Primary mouse hepatocytes and HepG2 cells were treated with IL-1β. ABCA1 expression was assessed by Western blotting and RT-qPCR, and ABCA1 promoter activity was examined using luciferase reporter assays with inhibitors targeting phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (p38 MAPK), or an H-89-sensitive pathway. Prolactin regulatory element-binding protein (PREB) involvement was evaluated by nuclear protein analysis, PREB-binding-site mutation, and siRNA-mediated knockdown. Lipid accumulation was assessed by intracellular cholesterol measurement and Oil Red O staining. IL-1β decreased ABCA1 protein and mRNA expression in a dose- and time-dependent manner and suppressed ABCA1 promoter activity. Inhibition of p38 MAPK or treatment with H-89 attenuated IL-1β-induced suppression of promoter activity and endogenous ABCA1 expression. Representative immunoblotting showed that IL-1β enhanced p38 MAPK phosphorylation, whereas SB203580 attenuated this response. IL-1β reduced nuclear PREB expression, and p38 MAPK inhibition restored nuclear PREB expression. Mutation of the PREB-binding site or PREB knockdown abolished IL-1β-mediated suppression of ABCA1 expression. IL-1β also increased intracellular cholesterol content and Oil Red O-positive lipid accumulation. These findings suggest that IL-1β suppresses hepatic ABCA1 expression through p38 MAPK signaling and an H-89-sensitive pathway, at least partly involving PREB-associated transcriptional regulation, and that this suppression is associated with hepatocellular lipid accumulation.
SN - 1348-4540
SN - 0918-8959
ER -