Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b
Suraj J Patel 1 2 3 4 5, Nan Liu 4 6 7 8, Sam Piaker 2 3, Anton Gulko 2, Maynara L Andrade 2, Frankie D Heyward 2 4 9, Tyler Sermersheim 2, Nufar Edinger 2 4, Harini Srinivasan 2 4, Margo P Emont 2 4, Gregory P Westcott 2 4, Jay Luther 3, Raymond T Chung 3, Shuai Yan 2 4, Manju Kumari 10, Reeby Thomas 11, Yann Deleye 12, André Tchernof 13, Phillip J White 12 14, Guido A Baselli 15 16, Marica Meroni 17, Dario F De Jesus 4 18, Rasheed Ahmad 11, Rohit N Kulkarni 4 9 18, Luca Valenti 15 16, Linus Tsai 2 4 9, Evan D Rosen 2 4 9
Affiliations
Affiliations
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA.
- Harvard Medical School, Boston, MA 02115, USA.
- Division of Digestive and Liver Diseases, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
- Cancer and Blood Disorders Center, Dana Farber Cancer Institute and Boston Children's Hospital, Boston, MA 02215, USA.
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China.
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
- Department of Cardiology, Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
- Immunology and Microbiology Department, Dasman Diabetes Institute, Kuwait City, Kuwait.
- Duke Molecular Physiology Institute and Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
- Institut Universitaire de Cardiologie and Pneumologie de Québec-Université Laval (IUCPQ-UL), Québec City, Canada.
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
- Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy.
- Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
- General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
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 AMPKα 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.
Conflict of interest statement
Competing interests: A.T. receives funding from Johnson & Johnson, Medtronic, and GI Windows for studies related to bariatric surgery, as well as consulting fees from Bausch Health, Novo Nordisk, and Eli Lilly. The other authors declare that they have no competing interests.
References
https://pubmed.ncbi.nlm.nih.gov/