The lack of apoA-I in apoE-KO mice affects the liver transcriptome

Background and aims: Liver is the major organ involved in apoA-I synthesis and HDL-C turnover, but the impact of apoA-I/HDL on hepatic transcriptome has never been investigated before. In the present study, a transcriptomic analysis by high-throughput RNA-seq was conducted in the liver of atherosclerosis-prone mice, with the aim of identifying new genes/pathways modulated by apoA-I/HDL with a potential effect on atherosclerosis development. Methods and results: Eight-week-old apoE knockout (apoEKO) mice lacking apoA-I/HDL (DKO) and with physiological levels of apoA-I/HDL (DKO/hA-I) were fed either a standard rodent diet (SRD) or a Western diet (WD) for 22 weeks. After both dietary treatments, DKO mice were characterized by lower cholesterol levels, but increased atherosclerosis development, compared to DKO/hA-I mice. The liver transcriptome of DKO and DKO/hA-I mice fed SRD diverged in a relatively small number of genes, suggestive of a greater activation of the PPAR signaling pathway and the retinoid metabolism pathway in DKO/hA-I mice. Following WD, transcriptomic analysis highlighted in both genotypes an upregulated expression of immune/inflammatory genes and a reduced activation of the retinoid metabolism. The evaluation of the hepatic response of the two genotypes to the dietary switch from SRD to WD revealed strong divergences in genes involved in metabolic pathways only in the presence of apoA-I/HDL, with reduced endogenous sterol biosynthesis and glutathione metabolism, together with increased glucose metabolism. Conclusion: The presence or absence of apoA-I expression differently alters hepatic pathways involved not only in cholesterol metabolism, but also in those of glutathione and glucose metabolism.