Apolipoprotein A-I Influences The Transcriptional Profile Of Fatty Liver In Apolipoprotein E Knockout 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/hA-I) were fed either a standard rodent diet (SRD) or a Western diet (WD) for 22 weeks. Steatosis was quantified, and the hepatic transcriptome was analyzed by RNAseq. Following WD, both genotypes showed marked lipid accumulation in the liver, without relevant histological differences. The transcriptome analysis showed an upregulated expression of immune/inflammatory genes and a reduced activation of the retinoid metabolism in both WD-fed genotypes. Strong divergences in genes involved in metabolic pathways were observed only in the presence of apoA-I/HDL, where the results suggested reduced endogenous biosynthesis of cholesterol and other sterols, glutathione metabolism 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, that goes beyond cholesterol metabolism.