The Na+-taurocholate cotransporting polypeptide knockout mouse: A new tool for study of bile acids and hepatitis B virus biology

摘要: The Na+-Taurocholate cotransporting polypeptide (NTCP; gene symbol SLC10A1) was cloned in 1991 and shown to function a sodium-dependent fashion efficiently take up all the major glycine taurine-conjugated bile acids.1 NTCP only weakly transports unconjugated acids, subsequent years, members of Organic Anion Transporting Polypeptide (OATP/SLCO) family facilitative carriers such as OATP1B1 OATP1B3 humans Oatp2b1 mice were identified transporters responsible for hepatic sodium-independent uptake particularly species. NTCP’s properties clearly established it candidate mechanism acid multiple However definitive vivo support lacking until recently when pediatric patient described with loss-of-function mutation highly elevated serum levels conjugated acids.2 Although child currently exhibits no jaundice, pruritus, or other signs liver disease, finding also highlighted gaps our ability predict long-term physiologic metabolic consequences reduced clearance. Following closely on heels first human case an isolated defect partially filling that void, Slijpcevic et al now report phenotypic characterization Slc10a1 knockout mouse.3 In brief, after confirming absence mRNA protein liver, authors used freshly hepatocytes sandwich cultures demonstrate taurocholate transport abolished Slc10a1−/− mice. Given observation, expected Slc10a1-deficient would exhibit markedly (hypercholanemia) similar NTCP-deficient patient. Surprisingly, normal range (1 20 μM) majority (~70%) mice, remaining subpopulation exhibiting dramatically (> 1000 μM). intermediate acids not evident, heterogeneity explained by gender mouse strain genetic background. studies then proceeded tell tale these two phenotypes. Overall, grossly their wild type littermates except body weights, common observation models defects biosynthetic enzymes important enterohepatic circulation acids. weight evident those highest levels. There hepatomegaly histological evidence injury; markers unremarkable normocholanemic but hypercholanemic In clearance intravenously administered slowed compared could be unmasked feeding diet containing ursodeoxycholic acid. Bile synthesis cycling appeared relatively unperturbed changes flow, biliary secretion, fecal excretion. contrast, exhibited more substantial clearance, well decreased excretion, increased urinary excretion. Overall, results generally concept NTCP/Slc10a1 is transporter However, observed raises questions regarding alternate mechanisms. preferentially may sufficiently active compensate prevent rise Indeed, several Oatps including Oatp1b2. But did strictly correlate presence hypercholanemia, additional unidentified modifiers phenotype involved. Comparison index NTCP-deficiency suggests compensatory mechanisms are engaged humans. This include higher hepatocyte Oatp1b2 (or another Oatp family), greater proportion being involved (pericentral/zone III periportal/zone I acinus). Additional analysis both Slco1b2 (Oatp2b1) will needed explore addition, known if fully penetrant Only single hypercholanemia has been described, even though non-functional variants have turned population-based sequencing studies.4 As such, existence subjects cannot excluded. In addition transporter, cell surface receptor Hepatitis B virus (HBV) Delta (HDV).5 HBV infection initiated via low affinity binding small heparin-sulfate proteoglycans attachment basolateral membrane hepatocytes. next step high-affinity occurs between host allows viral cellular entry. identity entry receptor(s) had long remained mystery. An breakthrough came Yan demonstrated large pre-S1 domain myristoylated peptide (amino 2–48) essential hepatocytes.5 Much work characterize HBV-NTCP interactions performed using domain-derived lipopeptide Myrcludex-B, provided new opportunity further role Ntcp binding. positron emission tomography imaging showed administration, radiolabeled Myrcludex B-derived peptides enriched wild-type absent from key receptor. It should noted binds does allow infections vitro.6 Nor introduction confer susceptibility hepatoma lines.6 utility dissect unclear. dual functions NCTP preS1 raised question whether there mutual interference. vitro inhibited NTCP, whereas blocked/inhibited infection.6,7 findings chimeric supported limits leads metabolism.8 model prove useful platform induced HBV. Altogether, description Slc10a1-knockout supportive central preS1/Myrcludex vivo. Slijepcevic provides valuable tool understanding complex intersection HBV, function.