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 i...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-04-01
|
| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3003112 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849311261381099520 |
|---|---|
| author | Marion Régnier Arnaud Polizzi Tiffany Fougeray Anne Fougerat Prunelle Perrier Karen Anderson Yannick Lippi Sarra Smati Céline Lukowicz Frédéric Lasserre Edwin Fouche Marine Huillet Clémence Rives Blandine Tramunt Claire Naylies Géraldine Garcia Elodie Rousseau-Bacquié Justine Bertrand-Michel Cécile Canlet Sylvie Chevolleau-Mege Laurent Debrauwer Christophe Heymes Rémy Burcelin Thierry Levade Pierre Gourdy Walter Wahli Yuna Blum Laurence Gamet-Payrastre Sandrine Ellero-Simatos Julie Guillermet-Guibert Phillip Hawkins Len Stephens Catherine Postic Alexandra Montagner Nicolas Loiseau Hervé Guillou |
| author_facet | Marion Régnier Arnaud Polizzi Tiffany Fougeray Anne Fougerat Prunelle Perrier Karen Anderson Yannick Lippi Sarra Smati Céline Lukowicz Frédéric Lasserre Edwin Fouche Marine Huillet Clémence Rives Blandine Tramunt Claire Naylies Géraldine Garcia Elodie Rousseau-Bacquié Justine Bertrand-Michel Cécile Canlet Sylvie Chevolleau-Mege Laurent Debrauwer Christophe Heymes Rémy Burcelin Thierry Levade Pierre Gourdy Walter Wahli Yuna Blum Laurence Gamet-Payrastre Sandrine Ellero-Simatos Julie Guillermet-Guibert Phillip Hawkins Len Stephens Catherine Postic Alexandra Montagner Nicolas Loiseau Hervé Guillou |
| author_sort | Marion Régnier |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b5f70b36b3fb49ec9d7b6db46f538fa5 |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-b5f70b36b3fb49ec9d7b6db46f538fa52025-08-20T03:53:27ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852025-04-01234e300311210.1371/journal.pbio.3003112Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling.Marion RégnierArnaud PolizziTiffany FougerayAnne FougeratPrunelle PerrierKaren AndersonYannick LippiSarra SmatiCéline LukowiczFrédéric LasserreEdwin FoucheMarine HuilletClémence RivesBlandine TramuntClaire NayliesGéraldine GarciaElodie Rousseau-BacquiéJustine Bertrand-MichelCécile CanletSylvie Chevolleau-MegeLaurent DebrauwerChristophe HeymesRémy BurcelinThierry LevadePierre GourdyWalter WahliYuna BlumLaurence Gamet-PayrastreSandrine Ellero-SimatosJulie Guillermet-GuibertPhillip HawkinsLen StephensCatherine PosticAlexandra MontagnerNicolas LoiseauHervé GuillouInsulin 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.https://doi.org/10.1371/journal.pbio.3003112 |
| spellingShingle | Marion Régnier Arnaud Polizzi Tiffany Fougeray Anne Fougerat Prunelle Perrier Karen Anderson Yannick Lippi Sarra Smati Céline Lukowicz Frédéric Lasserre Edwin Fouche Marine Huillet Clémence Rives Blandine Tramunt Claire Naylies Géraldine Garcia Elodie Rousseau-Bacquié Justine Bertrand-Michel Cécile Canlet Sylvie Chevolleau-Mege Laurent Debrauwer Christophe Heymes Rémy Burcelin Thierry Levade Pierre Gourdy Walter Wahli Yuna Blum Laurence Gamet-Payrastre Sandrine Ellero-Simatos Julie Guillermet-Guibert Phillip Hawkins Len Stephens Catherine Postic Alexandra Montagner Nicolas Loiseau Hervé Guillou Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling. PLoS Biology |
| title | Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling. |
| title_full | Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling. |
| title_fullStr | Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling. |
| title_full_unstemmed | Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling. |
| title_short | Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling. |
| title_sort | liver gene expression and its rewiring in hepatic steatosis are controlled by pi3kα dependent hepatocyte signaling |
| url | https://doi.org/10.1371/journal.pbio.3003112 |
| work_keys_str_mv | AT marionregnier livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT arnaudpolizzi livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT tiffanyfougeray livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT annefougerat livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT prunelleperrier livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT karenanderson livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT yannicklippi livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT sarrasmati livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT celinelukowicz livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT fredericlasserre livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT edwinfouche livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT marinehuillet livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT clemencerives livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT blandinetramunt livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT clairenaylies livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT geraldinegarcia livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT elodierousseaubacquie livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT justinebertrandmichel livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT cecilecanlet livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT sylviechevolleaumege livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT laurentdebrauwer livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT christopheheymes livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT remyburcelin livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT thierrylevade livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT pierregourdy livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT walterwahli livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT yunablum livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT laurencegametpayrastre livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT sandrineellerosimatos livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT julieguillermetguibert livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT philliphawkins livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT lenstephens livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT catherinepostic livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT alexandramontagner livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT nicolasloiseau livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling AT herveguillou livergeneexpressionanditsrewiringinhepaticsteatosisarecontrolledbypi3kadependenthepatocytesignaling |