Régnier Marion, Polizzi Arnaud, Fougeray Tiffany, Fougerat Anne, Perrier Prunelle, Anderson Karen, Lippi Yannick, Smati Sarra, Lukowicz Céline, Lasserre Frédéric, Fouche Edwin, Huillet Marine, Rives Clémence, Tramunt Blandine, Naylies Claire, Garcia Géraldine, Rousseau-Bacquié Elodie, Bertrand-Michel Justine, Canlet Cécile, Chevolleau-Mege Sylvie, Debrauwer Laurent, Heymes Christophe, Burcelin Rémy, Levade Thierry, Gourdy Pierre, Wahli Walter, Blum Yuna, Gamet-Payrastre Laurence, Ellero-Simatos Sandrine, Guillermet-Guibert Julie, Hawkins Phillip, Stephens Len, Postic Catherine, Montagner Alexandra, Loiseau Nicolas, Guillou Hervé
Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR1331, Université de Toulouse, Toulouse, France.
Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.
PLoS Biol. 2025 Apr 14;23(4):e3003112. doi: 10.1371/journal.pbio.3003112. eCollection 2025 Apr.
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.
胰岛素和其他生长因子是肝脏基因表达的关键调节因子，包括在代谢性疾病中。胰岛素诱导的大多数磷酸肌醇3激酶（PI3K）活性被认为依赖于PI3Kα。我们使用缺乏PI3Kα催化亚基p110α的小鼠，来研究其在健康状态以及代谢功能障碍相关脂肪性肝病（MASLD）中对肝脏基因表达调控的作用。肝细胞PI3Kα的缺失降低了最大胰岛素诱导的PI3K活性和信号传导，导致瘦小鼠出现葡萄糖不耐受，并在自由采食情况下显著调节肝脏基因表达，包括胰岛素敏感基因。肝细胞特异性胰岛素受体缺失后基因表达调控方面的一些缺陷与PI3Kα信号传导有关。此外，虽然肝细胞中PI3Kα的缺失会促进胰岛素抵抗，但在饮食诱导的肥胖中它对脂肪性肝病具有保护作用。在缺乏肝细胞PI3Kα的情况下，饮食诱导的肥胖对肝脏基因表达的影响发生了显著改变，肝脏中有节律的基因表达也出现了变化。总之，这项研究突出了p110α在生理状态下以及MASLD期间发生的代谢重编程过程中对肝脏基因表达控制的特定作用。
