We next sought to assess whether HLC eGenes and ASE genes are functional for lipid metabolism in mouse models. We used adeno-associated virus (AAV) serotype 8, which effectively transduces mouse hepatocytes in vivo, to heterologously express candidate genes from the liver-specific TBG promoter. We first assessed the candidate genes in the CPNE1/ERGIC3 locus, for which CPNE1 had stronger evidence of being a hepatocyte eGene than ERGIC3 (see above). We found that CPNE1 but not ERGIC3 reproducibly decreased blood HDL-C levels when overexpressed in mouse liver with AAV (Figure 6A), establishing CPNE1 as a lipid-functional gene. In the ANGPTL3/DOCK7 locus, we confirmed ANGPTL3 to be a lipid-functional gene by using CRISPR-Cas9 to delete the entire ANGPTL3 gene in mice and observing substantial decreases in both TG and cholesterol levels (Figure 6B).
