Abstract

The apical Na+-dependent bile salt transporter (ASBT/SLC10A2) is essential for maintaining the enterohepatic circulation of bile salts. It is not known when Slc10a2 evolved as a bile salt transporter or how it adapted to substantial changes in bile salt structure during evolution. We characterized ASBT orthologs from two primitive vertebrates, the lamprey that utilizes early 5α-bile alcohols and the skate that utilizes structurally different 5β-bile alcohols, and compared substrate specificity with ASBT from humans who utilize modern 5β-bile acids. Everted gut sacs of skate but not the more primitive lamprey transported 3H-taurocholic acid (TCA), a modern 5β-bile acid. However, molecular cloning identified ASBT orthologs from both species. Cell-based assays using recombinant ASBT/Asbt's indicate that lamprey Asbt has high affinity for 5α-bile alcohols, low affinity for 5β-bile alcohols, and lacks affinity for TCA, whereas skate Asbt showed high affinity for 5α- and 5β-bile alcohols but low affinity for TCA. In contrast, human ASBT demonstrated high affinity for all three bile salt types. These findings suggest that ASBT evolved from the earliest vertebrates by gaining affinity for modern bile salts while retaining affinity for older bile salts. Also, our results indicate that the bile salt enterohepatic circulation is conserved throughout vertebrate evolution.

Highlights

  • IntroductionBile salts play critical physiological roles in vertebrates

  • Supplementary key words sodium-dependent transporter enterohepatic circulation bile acids bile alcohols taurocholic acid lamprey petromyzon marinus skate leucoraja erinacea

  • When Na+ was replaced by choline in the medium, uptake of 3H-taurocholic acid (TCA) was abolished, indicating that a Na+-dependent bile salt transporter was present in the distal intestine of skate

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Summary

Introduction

Bile salts play critical physiological roles in vertebrates. They facilitate lipid absorption, inhibit microbe growth in the biliary tract and intestine, and function as signaling molecules that regulate energy expenditure and carbohydrate and lipid metabolism [2]. The bile salt pool is maintained in an enterohepatic circulation by bile salt transporters in the distal ileum and the liver [3] Central to this process is the apical sodium (Na+)-dependent bile salt transporter (ASBT/SLC10A2) located on the luminal membrane in the distal ileum and proximal tubule of the kidney in humans and rodents [4]. ASBT maintains the enterohepatic and renal-hepatic circulation of bile salts by facilitating their reabsorption from the intestinal lumen and renal tubules.

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