RNA Sequencing of livers from ApoE-/- mice treated with HIF1a inhibitor PX-478 or Saline

Purpose: HIF1a inhibitor PX-478 prevents hypercholesterolemia in ApoE-/- mice fed Western diet for 3 months. The goal of this study was to determine the mechanisms in the liver through which PX-478 regulates cholesterol. Methods: 4-week old ApoE-/- mice were fed a Western diet and injected intraperitoneally, bi-weekly with either PX-478 (40 mg/kg) or Saline for 3 months. The livers of 3 PX-478-treated mice and 4 Saline-treated mice were used for this RNA-seq study. Results: We identified 800+ differentially expressed genes in the PX-478-treated ApoE-/- mice livers relative to the saline-treated control livers. A subset of these genes were found to play important roles in cholesterol regulation and were further validated by qPCR analysis. Conclusions: Our study details potential hepatic cholesterol regulating mechanisms for HIF1a inhibitor PX-478. These results, coupled with our findings on the effect of PX-478 on two different mouse models of atherosclerosis, demonstrate that PX-478 is a potential anti-atherogenic and anti-hypercholesterolemic drug. Overall design: Liver mRNA profiles of ApoE-/- mice fed Western diet for 3 months and treated bi-weekly via IP injection with either Saline (n=4) or PX-478 (40 mg/kg, n=3)