Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling
Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is considered to be dependent on PI3Kα. We used mice lacking p110α, the catalytic subunit of PI3Kα, to investigate its role in the regulation of liver gene expression in health and in metabolic dysfunction-associated steatotic liver disease (MASLD). The absence of hepatocyte PI3Kα reduced maximal insulin-induced PI3K activity and signaling, promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, in ad libitum feeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3Kα signaling. In addition, though PI3Kα deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3Kα, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Altogether, this study highlights the specific role of p110α in the control of liver gene expression in physiology and in the metabolic rewiring that occurs during MASLD.
Authors
- Sandrine Ellero‐Simatos (ORCID: https://orcid.org/0000-0002-9282-1804)
- Walter Wahli (ORCID: https://orcid.org/0000-0002-5966-9089)
- Marion Régnier (ORCID: https://orcid.org/0000-0002-5005-0597)
- Sarra Smati (ORCID: https://orcid.org/0000-0002-5749-983X)
- Anne Fougerat (ORCID: https://orcid.org/0009-0000-0305-1880)
- Laurent Debrauwer (ORCID: https://orcid.org/0000-0003-3600-0902)
- Céline Lukowicz
- Len Stephens (ORCID: https://orcid.org/0000-0002-2771-3487)
- Phillip T. Hawkins (ORCID: https://orcid.org/0000-0002-6979-0464)
- Alexandra Montagner (ORCID: https://orcid.org/0000-0002-4800-5105)
- Julie Guillermet‐Guibert (ORCID: https://orcid.org/0000-0003-3173-4907)
- Laurence Gamet‐Payrastre (ORCID: https://orcid.org/0000-0003-1681-8491)
- Prunelle Perrier
- Rémy Burcelin (ORCID: https://orcid.org/0000-0002-7942-8346)
- Frédèric Lasserre (ORCID: https://orcid.org/0000-0001-5220-9787)
- Pierre Gourdy (ORCID: https://orcid.org/0000-0002-5362-3813)
- Arnaud Polizzi (ORCID: https://orcid.org/0000-0003-1986-2770)
- Justine Bertrand‐Michel (ORCID: https://orcid.org/0000-0001-9815-1517)
- Catherine Postic (ORCID: https://orcid.org/0000-0002-1875-6960)
- Clémence Rives
- Blandine Tramunt (ORCID: https://orcid.org/0009-0001-4020-3019)
- Claire Naylies
- Yannick Lippi (ORCID: https://orcid.org/0000-0003-4717-078X)
- Karen E. Anderson (ORCID: https://orcid.org/0000-0002-7394-6660)
- Thierry Levade (ORCID: https://orcid.org/0000-0003-3793-2584)
- Edwin Fouché
- Cécile Canlet (ORCID: https://orcid.org/0000-0002-6389-0712)
- Christophe Heymes (ORCID: https://orcid.org/0000-0002-6666-6193)
- Tiffany Fougeray
- Marine Huillet (ORCID: https://orcid.org/0000-0002-6508-4351)
- Hervé Guillou (ORCID: https://orcid.org/0000-0002-5363-9081)
- Elodie Rousseau-Bacquié (ORCID: https://orcid.org/0000-0002-4580-9036)
- Nicolas Loiseau (ORCID: https://orcid.org/0000-0003-3783-0879)
- Yuna Blum (ORCID: https://orcid.org/0000-0002-4716-8017)
- Sylvie Chevolleau-Mege
- Géraldine Garcia
Institutions
- Centre National de la Recherche Scientifique (FR)
- Babraham Institute (GB)
- Inserm (FR)
- Nanyang Technological University (SG)
- École Nationale Vétérinaire de Toulouse (FR)
- Université Paris Cité (FR)
- Centre Hospitalier Universitaire de Toulouse (FR)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Toxicologie Alimentaire (FR)
- Institut de génétique et de développement de Rennes (FR)
- Institut Cochin (FR)
- Institut des Maladies Métaboliques et Cardiovasculaires (FR)
- Université de Rennes (FR)
- University of Lausanne (CH)
Publication Details
- Journal
- PLoS Biology
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1371/journal.pbio.3003112
- Citations
- 1
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.35
Funders
- Agence Nationale de la Recherche
- École Polytechnique Fédérale de Lausanne
- Fondation pour la Recherche Médicale
- Fondation de France
- Université de Toulouse
- Institut National Du Cancer
- Région Occitanie Pyrénées-Méditerranée
- AgreenSkills