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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Oster, M; Galhuber, M; Krstic, J; Steinhoff, JS; Lenihan-Geels, G; Wulff, S; Kiefer, MF; Petricek, KM; Wowro, SJ; Flores, RE; Yang, N; Li, C; Meng, Y; Reinisch, I; Sommerfeld, M; Weger, S; Habisch, H; Madl, T; Schulz, TJ; Prokesch, A; Schupp, M.
Hepatic p53 is regulated by transcription factor FOXO1 and acutely controls glycogen homeostasis.
J Biol Chem. 2022; 298(9):102287 Doi: 10.1016/j.jbc.2022.102287 [OPEN ACCESS]
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Co-Autor*innen der Med Uni Graz
Galhuber Markus
Habisch Hansjörg
Krstic Jelena
Madl Tobias
Prokesch Andreas
Reinisch Isabel Nadine

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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.
Find related publications in this database (using NLM MeSH Indexing)
Animals - administration & dosage
Forkhead Box Protein O1 - genetics, metabolism
Gene Deletion - administration & dosage
Glucose - metabolism
Hepatocytes - metabolism
Homeostasis - administration & dosage
Insulin - metabolism
Liver - metabolism
Liver Glycogen - metabolism
Mice - administration & dosage
Triglycerides - metabolism
Tumor Suppressor Protein p53 - genetics, metabolism

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