Induction of human CYP4A11 gene expression by fasting or peroxisome proliferator activated receptor alpha (PPARa) agonists in transgenic mice

Abstract

Transgenic mice (CYP4A11‐Tg) were generated to examine regulation of the human CYP4A11 gene by PPARa agonists and fasting in vivo. Expression of the CYP4A11 transgene in mice gave liver and kidney CYP4A11 protein levels similar to those found in the corresponding human tissues. Fasted CYP4A11‐Tg exhibited a 2‐ to 3‐fold increase in hepatic CYP4A11 mRNA and protein as measured by qPCR and Western blots, respectively. Treatment with PPARa agonists, fenofibrate or clofibric acid, produced 2‐ to 4‐fold increases in hepatic CYP4A11 mRNA and protein. Collectively, these data show that fasting and PPARa agonists enhance CYP4A11 gene expression in CYP4A11‐Tg. The role of PPARa in this process was then tested in CYP4A11‐Tg that carried PPARa−/+ or PPARa−/− genotypes. Hepatic P450 4A11 protein and mRNA were induced 2‐fold by fenofibrate in PPARa−/+ CYP4A11‐Tg. Constitutive CYP4A11 levels were dramatically reduced (> 95%) in PPARa−/− females compared to PPARa−/+ females, whereas male PPARa−/− CYP4A11‐Tg retained >60% of the levels found in PPARa−/+ males. As neither CYP4A11 mRNA nor protein was inducible by fenofibrate in male or female PPARa−/− CYP4A11‐Tg, our data suggest that PPARa mediates induction of the CYP4A11 transgene by fenofibrate. Supported by NIH grants HD04445 (EFJ), GM49135 (RHT), and AA07842 (JML).