Effect of apolipoprotein A-I on the liver transcriptome of apolipoprotein E knock-out mice

Fatty liver disease is a condition characterized by lipid accumulation in the hepatocytes and it is generally accompanied by a dyslipidemic condition characterized by low HDL levels. Being the interrelation between fatty liver disease and low HDL not clearly understood, in the present study, the impact of different apoA-I/HDL levels on the transcriptome of diet-induced fatty liver was investigated. Eight-week-old mice lacking apoA-I/HDL (DKO)and mice with physiological levels of apoA-I/HDL (DKO/hAI) were fed either a standard rodent diet (SRD) or a Western diet (WD) for 22 weeks. Steatosis was evaluated, and the hepatic transcriptome was analyzed by RNAseq. The lack of apoA-I/HDL in DKO mice fed SRD was not associated to hepatic histological alterations. The 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 retinol metabolism pathway in DKO/hA-I mice. Following WD, both genotypes comparably showed marked lipid accumulation in the liver. Transcriptomic analysis highlighted an upregulated expression of immune/inflammatory genes and a reduced activation of the retinoid metabolism in both DKO andDKO/hA-I mice. 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, together with increased glucose metabolism. In conclusion, although not histologically overt, apoA-I/HDL seems to exert a substantial impact on hepatic metabolism during steatosis.