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Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is considered to be dependent on PI3K\u03b1. We used mice lacking p110\u03b1, the catalytic subunit of PI3K\u03b1, 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 PI3K\u03b1 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 <jats:italic>ad libitum<\/jats:italic> feeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3K\u03b1 signaling. In addition, though PI3K\u03b1 deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3K\u03b1, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. 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