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The <i>SERPINA1</i> gene encodes alpha1-antitrypsin (AAT), an acute phase glycoprotein and serine protease inhibitor that is mainly (80–90%) produced in the liver. Point mutations in the <i>SERPINA1</i> gene can lead to the misfolding, intracellular accumulation, and deficiency of circulating AAT protein, increasing the risk of developing chronic liver diseases or chronic obstructive pulmonary disease. Currently, siRNA technology can knock down the <i>SERPINA1</i> gene and limit defective AAT production. How this latter affects other liver genes is unknown. Livers were taken from age- and sex-matched C57BL/6 wild-type (WT) and <i>Serpina1</i> knockout mice (KO) aged from 8 to 14 weeks, all lacking the five serpin A1a-e paralogues. Total RNA was isolated and RNA sequencing, and transcriptome analysis was performed. The knockout of the <i>Serpina1</i> gene in mice changed inflammatory, lipid metabolism, and cholesterol metabolism-related gene expression in the liver. Independent single-cell sequencing data of WT mice verified the involvement of <i>Serpina1</i> in cholesterol metabolism. Our results from mice livers suggested that designing therapeutic strategies for the knockout of the <i>SERPINA1</i> gene in humans must account for potential perturbations of key metabolic pathways and consequent mitigation of side effects.