Insulin transcriptionally down-regulates carboxylesterases through pregnane X receptor in an Akt-dependent manner.

Insulin is a major therapy for diabetes, and therefore, its role and mechanisms in the regulation of drug-metabolizing enzymes (DMEs), is of clinical importance to facilitate the rational drug use. Carboxylesterases are regarded as one of the major determinants of the metabolism and disposition of various substrates through their actions in the liver and intestine, alterations in the activity of CESs enzymes are often important causes of drug interactions. Therefore, investigation on the mechanism of CESs regulation is significantly important. In this study, we demonstrated that insulin markedly down-regulated CESs expression and suppressed the hydrolytic activity of CESs in an Akt-dependent manner. Moreover, overexpression of PXR abrogated the decrease of CES1 and CES2 expression induced by insulin in HepG2 cells, suggesting PXR was involved in insulin-induced reduction of CESs. Mechanistically, luciferase reporter assay showed that PXR increased the transcriptional activity of CES1 and CES2 gene promoter, and chromatin immunoprecipitation assay verified that PXR bound to the site (-244 to -234) in CES1 gene promoter region and bound to the site (-814 to -804 and -794 to -784) in CES2 gene promoter region for the first time. In summary, our data indicate that down-regulation of PXR mediates insulin-induced suppression of CESs. Accordingly, insulin may impact the therapeutic effects of carboxylesterases substrate drugs and also inhibit expression of other genes targeted by PXR, thus inducing a wide range of potential drug-drug interactions (DDIs) during the treatment of diabetes.