Cyp26a1 supports post-natal retinoic acid homeostasis and glucoregulatory control.

Considerable evidence confirms the importance of Cyp26a1 to all-trans-retinoic acid (RA) homeostasis during embryogenesis. In contrast, despite its presence in post-natal liver as a potential major RA catabolizing enzyme, and its acute sensitivity to induction by RA, some data suggested that Cyp26a1 contributes only marginally to endogenous RA homeostasis postnatally. We report re-evaluation of a conditional Cyp26a1 knockdown in the postnatal mouse. The current results show that Cyp26a1 mRNA in wild-type (WT) mouse liver increases 16-fold upon re-feeding after a fast, accompanied by an increased rate of RA elimination and a 41% decrease in the RA concentration. In contrast, Cyp26a1 mRNA in the re-fed homozygotic knockdown reached only 2% of its extent in WT during re-feeding, accompanied by a slower rate of RA catabolism and no decrease in liver RA, relative to fasting. Re-fed homozygous knockdown mice also had decreased Akt1 and 2 phosphorylation and pyruvate dehydrogenase kinase 4 (Pdk4) mRNA, and increased glucokinase (Gck) mRNA, glycogen phosphorylase (Pygl) phosphorylation, and serum glucose, relative to WT. Fasted homozygous knockdown mice had increased glucagon/insulin relative to WT. These data indicate that Cyp26a1 participates prominently in moderating the post-natal liver concentration of endogenous RA, and contributes essentially to glucoregulatory control.