| Title: |
Alterations in zonal distribution and plasma membrane localization of hepatocyte bile acid transporters in patients with NAFLD |
| Authors: |
Murphy, William A.; Diehl, Anna Mae; Loop, Matthew Shane; Fu, Dong; Guy, Cynthia D.; Abdelmalek, Manal F.; Karachaliou, Georgia Sofia; Sjostedt, Noora; Neuhoff, Sibylle; Honkakoski, Paavo; Brouwer, Kim L. R. |
| Contributors: |
Divisions of Faculty of Pharmacy; Drug Research Program; Division of Pharmaceutical Biosciences; Transporter group |
| Publisher Information: |
John Wiley & Sons Ltd. |
| Publication Year: |
2024 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Induced liver-injury; Efflux transporters; Obeticholic acid; Drug; Expression; Multicenter; Progression; Risk; General medicine; internal medicine and other clinical medicine |
| Description: |
Background: NAFLD is highly prevalent with limited treatment options. Bile acids (BAs) increase in the systemic circulation and liver during NAFLD progression. Changes in plasma membrane localization and zonal distribution of BA transporters can influence transport function and BA homeostasis. However, a thorough characterization of how NAFLD influences these factors is currently lacking. This study aimed to evaluate the impact of NAFLD and the accompanying histologic features on the functional capacity of key hepatocyte BA transporters across zonal regions in human liver biopsies. Methods: A novel machine learning image classification approach was used to quantify relative zonal abundance and plasma membrane localization of BA transporters (bile salt export pump [BSEP], sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptides [OATP] 1B1 and OATP1B3) in non-diseased (n = 10), NAFL (n = 9), and NASH (n = 11) liver biopsies. Based on these data, membrane-localized zonal abundance (MZA) measures were developed to estimate transporter functional capacity. Results: NAFLD diagnosis and histologic scoring were associated with changes in transporter membrane localization and zonation. Increased periportal BSEPMZA (mean proportional difference compared to non-diseased liver of 0.090) and decreased pericentral BSEPMZA (-0.065) were observed with NASH and also in biopsies with higher histologic scores. Compared to Non-diseased Liver, periportal OATP1B3(MZA) was increased in NAFL (0.041) and NASH (0.047). Grade 2 steatosis (mean proportional difference of 0.043 when compared to grade 0) and grade 1 lobular inflammation (0.043) were associated with increased periportal OATP1B3(MZA). Conclusions: These findings provide novel mechanistic insight into specific transporter alterations that impact BA homeostasis in NAFLD. Changes in BSEPMZA likely contribute to altered BA disposition and pericentral microcholestasis previously reported in some patients with NAFLD. BSEPMZA assessment could inform ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
This work was supported by the 2020/2021 Certara Simcyp Grant and Partnership Scheme (William A.Murphy and Kim L. R. Brouwer), discretionary fundingfrom the Duke NAFLD Clinical-Translational Research Program, and the University of North Carolina at Chapel Hill-Duke Nannerl O. Keohane Distinguished Visiting Professorship (Paavo Honkakoski). William A. Murphyis also supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM086330 (University of North Carolina at Chapel Hill-Duke Collaborative Clinical Pharmacology T32 Postdoctoral Training Program). Method development and optimization wassupported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) underAward Number R35GM122576 (Kim L. R. Brouwer). Paavo Honkakoski was partially supported by the Academy of Finland, grant #332660.; Murphy, W A, Diehl, A M, Loop, M S, Fu, D, Guy, C D, Abdelmalek, M F, Karachaliou, G S, Sjostedt, N, Neuhoff, S, Honkakoski, P & Brouwer, K L R 2024, 'Alterations in zonal distribution and plasma membrane localization of hepatocyte bile acid transporters in patients with NAFLD', Hepatology communications, vol. 8, no. 3. https://doi.org/10.1097/HC9.0000000000000377; https://hdl.handle.net/10138/573403; 85196316905; 001162446600002 |
| Availability: |
https://hdl.handle.net/10138/573403 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.4B0B686 |
| Database: |
BASE |