Abstract
BackgroundSLC10A2-mediated reabsorption of bile acids at the distal end of the ileum is the first step in enterohepatic circulation. Because bile acids act not only as detergents but also as signaling molecules in lipid metabolism and energy production, SLC10A2 is important as the key transporter for understanding the in vivo kinetics of bile acids. SLC10A family members and the homologous genes of various species share a highly conserved region corresponding to Gly104–Pro142 of SLC10A2. The functional importance of this region has not been fully elucidated.ResultsTo elucidate the functional importance of this region, we previously performed mutational analysis of the uncharged polar residues and proline in the distal one-third (Thr130–Pro142) of the highly conserved region in mouse Slc10a2. In this study, proline and uncharged polar residues in the remaining two-thirds of this region in mouse Slc10a2 were subjected to mutational analysis, and taurocholic acid uptake and cell surface localization were examined. Cell surface localization of Slc10a2 is necessary for bile acid absorption. Mutants in which Asp or Leu were substituted for Pro107 (P107N or P107L) were abundantly expressed, but their cell surface localization was impaired. The S126A mutant was completely impaired in cellular expression. The T110A and S128A mutants exhibited remarkably enhanced membrane expression. The S112A mutant was properly expressed at the cell surface but transport activity was completely lost. Replacement of Tyr117 with various amino acids resulted in reduced transport activity. The degree of reduction roughly depended on the van der Waals volume of the side chains.ConclusionsThe functional importance of proline and uncharged polar residues in the highly conserved region of mouse Slc10a2 was determined. This information will contribute to the design of bile acid-conjugated prodrugs for efficient drug delivery or SLC10A2 inhibitors for hypercholesterolemia treatment.
Highlights
SLC10A2-mediated reabsorption of bile acids at the distal end of the ileum is the first step in enterohepatic circulation
In addition to the detergent action of bile acids, which aids in the digestion and absorption of lipid and lipid-soluble nutrients by forming micelles with biliary phospholipids and cholesterol, bile acids are appreciated as signaling molecules that control lipid metabolism and energy production [1,2,3,4,5,6]
Among the transporters that are expressed in the liver, intestine, and bile duct and are involved in enterohepatic circulation of bile acids, SLC10A2 is the key transporter for understanding the in vivo kinetics of bile acids given that reabsorption of bile acids by SLC10A2 is the first step in enterohepatic circulation
Summary
SLC10A2-mediated reabsorption of bile acids at the distal end of the ileum is the first step in enterohepatic circulation. Because bile acids act as detergents and as signaling molecules in lipid metabolism and energy production, SLC10A2 is important as the key transporter for understanding the in vivo kinetics of bile acids. At the distal end of the ileum, 95%–98% of bile acids are effectively reabsorbed by an ileal sodium-dependent bile acid transporter (SLC10A2, designated ASBT, ISBT, or IBAT) and returned to the liver via portal circulation. Among the transporters that are expressed in the liver, intestine, and bile duct and are involved in enterohepatic circulation of bile acids, SLC10A2 is the key transporter for understanding the in vivo kinetics of bile acids given that reabsorption of bile acids by SLC10A2 is the first step in enterohepatic circulation. Due to its high transport capacity in the ileum, SLC10A2 is an attractive target for the prodrug strategy to enhance drug bioavailability [11,12]
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