Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: Conjugated hypercholanemia without a clear clinical phenotype

Abstract

The enterohepatic circulation of bile salts is an important physiological route to recycle bile salts and ensure intestinal absorption of dietary lipids. The Na 1 -taurocholate cotransporting polypeptide SLC10A1 (NTCP) plays a key role in this process as the major transporter of conjugated bile salts from the plasma compartment into the hepatocyte. Here we present the first patient with NTCP deficiency, who was clinically characterized by mild hypotonia, growth retardation, and delayed motor milestones. Total bile salts in plasma were extremely elevated (up to 1,500 lM, ref. <16.3) but there were no clinical signs of cholestatic jaundice, pruritis, or liver dysfunction. Bile salt synthesis and intestinal bile salt signaling were not affected, as evidenced by normal plasma 7a-hydroxy-4-cholesten-3-one (C4) and FGF19 levels. Importantly, the presence of secondary bile salts in the circulation suggested residual enterohepatic cycling of bile salts. Sequencing of the SLC10A1 gene revealed a single homozygous nonsynonymous point mutation in the coding sequence of the gene, resulting in an arginine to histidine substitution at position 252. Functional studies showed that this mutation resulted in a markedly reduced uptake activity of taurocholic acid. Immunofluorescence studies and surface biotinylation experiments demonstrated that the mutant protein is virtually absent from the plasma membrane. Conclusion: We describe the identification of NTCP deficiency as a new inborn error of metabolism with a relatively mild clinical phenotype. The identification of NTCP deficiency confirms that this transporter is the main import system for conjugated bile salts into the liver but also indicates that auxiliary transporters are able to sustain the enterohepatic cycle in its absence. (HEPATOLOGY 2015;61:260-267)

Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response

“…Indeed, in the present study, BA uptake was diminished when Ntcp was inhibited, and resulted in less induction of Cxcl2 (Figure 4). Recently, a rare case of NTCP deficiency was described in which the patient was completely protected from cholestatic liver injury, despite extremely high levels of BAs in the blood, consistent with our findings (20). These observations also suggest that pharmacological inhibition of NTCP might be a novel therapy for patients with cholestasis.…”

“…To better understand why BA-stimulated cytokine production was hepatocyte specific, we speculated that the hepatocyte BA transporter, Ntcp (Slc10a1), may be required to mediate this event owing to its robust uptake of conjugated BA (20,21). As shown in Figure 4A, when Ntcp expression in mouse hepatocytes was knocked down by siRNAs, Cxcl2 induction by TCA was significantly diminished.…”

Regulation of Plasma Membrane Localization of the Na+-Taurocholate Cotransporting Polypeptide (Ntcp) by Hyperosmolarity and Tauroursodeoxycholate

“…Loss of Ntcp results in increased plasma levels of conjugated bile acids, as also confirmed by a recent report on human NTCP deficiency (31), which is clinically characterized by mild hypotonia, growth retardation, and delayed motor milestones. Functional studies show that the underlying mutation results in a markedly reduced uptake activity of taurocholate (TC), which is due to an absence of the mutant protein in the plasma membrane of the hepatocyte (31). Recent studies suggest that the cholestatic bile salt taurolithocholate inhibits hepatic TC uptake and decreases plasma membrane levels of Ntcp (32).…”

Age‐dependent glycosylation of the sodium taurocholate cotransporter polypeptide: From fetal to adult human livers

“…Alternatively, isoforms of the organic anion transporting polypeptides multispecific transporter family compensate for NTCP deficiency by internalizing conjugated and unconjugated BA (Na + ‐independent pathway) 9, 10. Patients with primary hypercholanemia have been described with relatively mild clinical phenotypes, which have also been associated with growth retardation and vitamin deficiency 11, 12. Interestingly, down‐regulation of plasma membrane NTCP was reported in cases of progressive familial intrahepatic cholestasis‐2 and ‐313 and was thought to be linked to NTCP posttranslational modifications.…”