Effects of patent ductus venosus on bile acid homeostasis in aryl hydrocarbon receptor (AhR)-null mice

Abstract

The Aryl hydrocarbon receptor (AhR) is primarily known as one of the xenosensors and regulators of drug-metabolizing genes. Bile acids (BAs) are synthesized in the liver, and undergo several enterohepatic recirculations in which the liver removes BAs from the portal blood, minimizing the BAs that spill over into the systemic circulation. Previous studies revealed a lifelong patent ductus venosus (PDV) in AhR-null mice. Increased concentration of total BAs (Σ-BAs) in AhR-null mice is known; however, the impact of PDV on BA homeostasis in liver and bile remains unclear. This work investigated the consequences of PDV on BA homeostasis by comparing AhR-null and wild-type (WT) mice of both genders. In serum, Σ-BAs were markedly higher (64-85-fold) in AhR-null mice than in WT mice, especially due to the increase of tri-OH primary BAs (86-142-fold). Despite the extremely high concentration of serum BAs, the concentration of BAs in livers of AhR-null mice remained similar to WT mice. AhR-null livers were protected against increased BA influx by downregulation of uptake transporters and BA synthetic enzymes in the alternative pathway. Although livers of AhR-null mice are 20-25% smaller than WT mice, biliary excretion of BAs was maintained in the AhR-null mice, and even tended to increase. Surprisingly, intestinal Fgf15 expression was not increased, even though there was a marked increase in serum BA concentrations. Although PDV resulted in extremely high BA concentrations in serum of AhR-null mice, they maintained a concentration of BAs in liver and biliary excretion of BAs similar to control mice.

Keywords: Aryl Hydrocarbon Receptor; Bile Acids; Biliary Excretion; Ductus Venosus.