p110α-dependent hepatocyte signaling is critical for liver gene expression and its rewiring in MASLD

Abstract

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 dependent on PI3Kα. We used mice lacking p110α, the catalytic subunit of PI3Kα, to investigate its role in the regulation of liver gene expression. The absence of hepatocyte PI3Kα signaling promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, inad libitumfeeding. 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. Therefore, this study highlights the specific role of membrane signaling dependent on hepatocyte PI3Kα in the control of liver gene expression in physiology and in Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD).HighlightsHepatocyte p110α is required for liver growth, glucose homeostasis, and regulation of liver gene expression.Hepatocyte p110α is dispensable for the regulation of carbohydrate sensing by ChREBP and fatty acid sensing by PPARα.Hepatocyte p110α-mediated regulation of gene expression is related to both insulin receptor-dependent and -independent pathways.Hepatocyte p110α is required for lipid homeostasis and the rewiring of gene expression that occurs during diet-induced obesity.