dc.contributor.author
Oster, Moritz
dc.contributor.author
Galhuber, Markus
dc.contributor.author
Krstic, Jelena
dc.contributor.author
Steinhoff, Julia S.
dc.contributor.author
Lenihan-Geels, Georgia
dc.contributor.author
Wulff, Sascha
dc.contributor.author
Kiefer, Marie F.
dc.contributor.author
Petricek, Konstantin M.
dc.contributor.author
Wowro, Sylvia J.
dc.contributor.author
Flores, Roberto E.
dc.contributor.author
Yang, Na
dc.contributor.author
Li, Chen
dc.contributor.author
Meng, Yueming
dc.contributor.author
Reinisch, Isabel
dc.contributor.author
Sommerfeld, Manuela
dc.contributor.author
Weger, Stefan
dc.contributor.author
Habisch, Hansjörg
dc.contributor.author
Madl, Tobias
dc.contributor.author
Schulz, Tim J.
dc.contributor.author
Prokesch, Andreas
dc.contributor.author
Schupp, Michael
dc.date.accessioned
2023-04-21T08:02:29Z
dc.date.available
2023-04-21T08:02:29Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/39047
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-38763
dc.description.abstract
The tumor suppressor p53 is involved in the adaptation of hepatic metabolism to nutrient availability. Acute deletion of p53 in the mouse liver affects hepatic glucose and triglyceride metabolism. However, long-term adaptations upon the loss of hepatic p53 and its transcriptional regulators are unknown. Here we show that short-term, but not chronic, liver-specific deletion of p53 in mice reduces liver glycogen levels, and we implicate the transcription factor forkhead box O1 protein (FOXO1) in the regulation of p53 and its target genes. We demonstrate that acute p53 deletion prevents glycogen accumulation upon refeeding, whereas a chronic loss of p53 associates with a compensational activation of the glycogen synthesis pathway. Moreover, we identify fasting-activated FOXO1 as a repressor of p53 transcription in hepatocytes. We show that this repression is relieved by inactivation of FOXO1 by insulin, which likely mediates the upregulation of p53 expression upon refeeding. Strikingly, we find that high-fat diet-induced insulin resistance with persistent FOXO1 activation not only blunted the regulation of p53 but also the induction of p53 target genes like p21 during fasting, indicating overlapping effects of both FOXO1 and p53 on target gene expression in a context-dependent manner. Thus, we conclude that p53 acutely controls glycogen storage in the liver and is linked to insulin signaling via FOXO1, which has important implications for our understanding of the hepatic adaptation to nutrient availability.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
glucose metabolism
en
dc.subject
triglycerides
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Hepatic p53 is regulated by transcription factor FOXO1 and acutely controls glycogen homeostasis
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
102287
dcterms.bibliographicCitation.doi
10.1016/j.jbc.2022.102287
dcterms.bibliographicCitation.journaltitle
Journal of Biological Chemistry
dcterms.bibliographicCitation.number
9
dcterms.bibliographicCitation.originalpublishername
Elsevier
dcterms.bibliographicCitation.volume
298
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
35868560
dcterms.isPartOf.eissn
1083-351X