Microarray analysis identifies human apoA-IMilano and apoA-II as determinants of the liver gene expression related to lipid and energy metabolism

The phenotype of individuals carrying the apolipoprotein A-IMilano (apoA-IM), the mutant form of human apoA-I (apoA-I), is characterized by very low concentrations of HDL and apoA-I, and hypertriglyceridemia. Paradoxically, these subjects are not found to be at increased risk of premature cardiovascular disease compared to controls. Besides, various in vitro and in vivo studies have demonstrated that apoA-IM possesses greater anti-atherosclerotic activity compared to apoA-I. The molecular mechanisms explaining the apoA-IM carrier's phenotype and the apoA-IM higher efficacy are still not fully elucidated. To investigate such mechanisms, we crossed previously generated apoA-I (A-I k-in) or apoA-IM knock-in mice (A-IM k-in) with transgenic mice expressing human apoA-II but lacking murine apoA-I (hA-II) to generate hA-II/A-I k-in, and hA-II/A-IM k-in, respectively. These genetically modified mice completely reproduced the apoA-IM carrier's phenotype, including hypoalphalipoproteinemia and hypertriglyceridemia. Furthermore, by using the microarray methodology, we investigated the intrinsic differences in hepatic gene expression among these k-in mouse lines. The expression of 871, 1,018, 1129 and 764 genes was significantly altered between 1) hA-II/A-I and hA-II/A-IM k-in; 2) A-IM and hA-II/A-IM k-in; 3) A-I and A-IM; 4) A-I and hA-II/A-I k-in liver samples, respectively. Bioinformatics analysis highlighted that the hepatic expression of two genes, Elovl6 and Gatm, related to fatty acid/lipid and energy metabolism, respectively, is influenced by the presence of the apoA-IM natural variant and/or apoA-II.