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Verfasst von:Patel, Suraj J. [VerfasserIn]   i
 Liu, Nan [VerfasserIn]   i
 Piaker, Sam [VerfasserIn]   i
 Gulko, Anton [VerfasserIn]   i
 Andrade, Maynara L. [VerfasserIn]   i
 Heyward, Frankie D. [VerfasserIn]   i
 Sermersheim, Tyler [VerfasserIn]   i
 Edinger, Nufar [VerfasserIn]   i
 Srinivasan, Harini [VerfasserIn]   i
 Emont, Margo P. [VerfasserIn]   i
 Westcott, Gregory P. [VerfasserIn]   i
 Luther, Jay [VerfasserIn]   i
 Chung, Raymond T. [VerfasserIn]   i
 Yan, Shuai [VerfasserIn]   i
 Kumari, Manju [VerfasserIn]   i
 Thomas, Reeby [VerfasserIn]   i
 Deleye, Yann [VerfasserIn]   i
 Tchernof, Andre [VerfasserIn]   i
 White, Phillip J. [VerfasserIn]   i
 Baselli, Guido A. [VerfasserIn]   i
 Meroni, Marica [VerfasserIn]   i
 De Jesus, Dario F. [VerfasserIn]   i
 Ahmad, Rasheed [VerfasserIn]   i
 Kulkarni, Rohit N. [VerfasserIn]   i
 Valenti, Luca [VerfasserIn]   i
 Tsai, Linus [VerfasserIn]   i
 Rosen, Evan D. [VerfasserIn]   i
Titel:Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b
Verf.angabe:Suraj J. Patel, Nan Liu, Sam Piaker, Anton Gulko, Maynara L. Andrade, Frankie D. Heyward, Tyler Sermersheim, Nufar Edinger, Harini Srinivasan, Margo P. Emont, Gregory P. Westcott, Jay Luther, Raymond T. Chung, Shuai Yan, Manju Kumari, Reeby Thomas, Yann Deleye, André Tchernof, Phillip J. White, Guido A. Baselli, Marica Meroni, Dario F. De Jesus, Rasheed Ahmad, Rohit N. Kulkarni, Luca Valenti, Linus Tsai, Evan D. Rosen
E-Jahr:2022
Jahr:March 23, 2022
Umfang:16 S.
Fussnoten:Gesehen am 30.01.2023
Titel Quelle:Enthalten in: Science translational medicine
Ort Quelle:Washington, DC : AAAS, 2009
Jahr Quelle:2022
Band/Heft Quelle:14(2022), 637, Artikel-ID eabh3831, Seite 1-16
ISSN Quelle:1946-6242
Abstract:Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b, a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia. Integration of the IRF3-dependent transcriptome and cistrome in mouse hepatocytes identifies Ppp2r1b as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of Ppp2r1b amplified PP2A activity, with subsequent dephosphorylation of AMPK. and AKT. Furthermore, suppression of hepatic Irf3 expression with antisense oligonucleotides reversed obesity-induced insulin resistance and restored glucose homeostasis in obese mice. Obese humans with NAFLD displayed enhanced activation of liver IRF3, with reversion after bariatric surgery. Hepatic PPP2R1B expression correlated with HgbA1C and was elevated in obese humans with impaired fasting glucose. We therefore identify the hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggest an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.
DOI:doi:10.1126/scitranslmed.abh3831
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

kostenfrei: Volltext: https://doi.org/10.1126/scitranslmed.abh3831
 kostenfrei: Volltext: https://www.science.org/doi/10.1126/scitranslmed.abh3831
 DOI: https://doi.org/10.1126/scitranslmed.abh3831
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:gene-expression
 nf-kappa-b
 activated protein-kinase
 antiinflammatory agents
 fatty liver-disease
 glucose-production
 insulin-resistance
 metabolic syndrome
 necrosis-factor-alpha
 nonalcoholic steatohepatitis
K10plus-PPN:1832663159
Verknüpfungen:→ Zeitschrift

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