Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b

• Published in: Science translational medicine Vol. 14; no. 637; p. eabh3831
• Main Authors: Patel, Suraj J, Liu, Nan, Piaker, Sam, Gulko, Anton, Andrade, Maynara L, Heyward, Frankie D, Sermersheim, Tyler, Edinger, Nufar, Srinivasan, Harini, Emont, Margo P, Westcott, Gregory P, Luther, Jay, Chung, Raymond T, Yan, Shuai, Kumari, Manju, Thomas, Reeby, Deleye, Yann, Tchernof, André, White, Phillip J, Baselli, Guido A, Meroni, Marica, De Jesus, Dario F, Ahmad, Rasheed, Kulkarni, Rohit N, Valenti, Luca, Tsai, Linus, Rosen, Evan D
• Format: Journal Article
• Language: English
• Published: United States 23.03.2022
• Subjects: Animals; Insulin Resistance - physiology; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Mice; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - genetics; Obesity - complications; Obesity - metabolism
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.abh3831

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 , 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 as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of amplified PP2A activity, with subsequent dephosphorylation of AMPKα and AKT. Furthermore, suppression of hepatic 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 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.