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Sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis

OBJECTIVE: Sodium(+)/ taurocholate cotransporting polypeptide (NTCP) is a membrane transporter affecting the enterohepatic circulation of bile acids (BAs). We aimed to evaluate NTCP’s roles in humans and animal models of liver fibrosis (LF). DESIGN: Primary hepatic stellate cells (pHSCs) isolated fr...

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Autores principales: Salhab, Ahmad, Amer, Johnny, Lu, Yinying, Safadi, Rifaat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9185811/
https://www.ncbi.nlm.nih.gov/pubmed/34266968
http://dx.doi.org/10.1136/gutjnl-2020-323345
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author Salhab, Ahmad
Amer, Johnny
Lu, Yinying
Safadi, Rifaat
author_facet Salhab, Ahmad
Amer, Johnny
Lu, Yinying
Safadi, Rifaat
author_sort Salhab, Ahmad
collection PubMed
description OBJECTIVE: Sodium(+)/ taurocholate cotransporting polypeptide (NTCP) is a membrane transporter affecting the enterohepatic circulation of bile acids (BAs). We aimed to evaluate NTCP’s roles in humans and animal models of liver fibrosis (LF). DESIGN: Primary hepatic stellate cells (pHSCs) isolated from livers biopsies of patients with LF with different fibrosis grading were stained for NTCP. NTCP gene silencing, taurocholic acid (TCA), obeticholic acid (OCA), epigallocatechin gallate (EGCG) and HA-100 dihydrochloride (HA-100) were used as tools to modulate NTCP expression on human HSC line (LX2). BA trafficking/uptake were assessed extracellularly (LX2 culture medium) and intracellularly following treatment with/without NTCP neutralizing antibody. LF models of C57/BL6 mice of carbon tetrachloride (CCl(4)) and leptin-deficient (Ob/Ob) fed with high-fat diet (Ob/Ob (HFD) ) were evaluated for pHSCs-NTCP expressions, metabolic and LF profiles following intraperitoneal injections of NTCP neutralizing antibody. RESULTS: pHSCs from F3/F4-scored patients of LF exhibit threefold increased NTCP expressions compared with F0-scored patients (p<0.0001). Sorted-activated HSCs (LX2(αSMA+)) showed high expressions of NTCP and high TCA uptake in vitro and triggered a further increase in their activations. This phenomenon was inhibited with NTCP small interfering RNA and the NTCP neutralizing antibody. Sorted LX2(NTCP+) (high alpha smooth muscle actin (αSMA)/high NTCP) cells showed high phosphorylated pathways of AKT/mTOR and protein kinase C (PKC) accompanied with a decrease in farnesoid X receptor expression. Moreover, LX2(NTCP+) cells treated with EGCG, OCA and PKC inhibitor HA-100 significantly decreased NTCP and αSMA. NTCP neutralizing antibody inhibited NTCP (less TCA uptake); it attenuated LF in both CCl(4) and Ob/Ob (HFD) animal models with ameliorated metabolic profile. CONCLUSION: NTCP expression is linearly correlated with fibrosis severity. Modulated BA trafficking could be an important step in LF pathogenesis. Antagonising BA uptake may suggest a therapeutic strategy for preventing disease progression.
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spelling pubmed-91858112022-06-16 Sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis Salhab, Ahmad Amer, Johnny Lu, Yinying Safadi, Rifaat Gut Hepatology OBJECTIVE: Sodium(+)/ taurocholate cotransporting polypeptide (NTCP) is a membrane transporter affecting the enterohepatic circulation of bile acids (BAs). We aimed to evaluate NTCP’s roles in humans and animal models of liver fibrosis (LF). DESIGN: Primary hepatic stellate cells (pHSCs) isolated from livers biopsies of patients with LF with different fibrosis grading were stained for NTCP. NTCP gene silencing, taurocholic acid (TCA), obeticholic acid (OCA), epigallocatechin gallate (EGCG) and HA-100 dihydrochloride (HA-100) were used as tools to modulate NTCP expression on human HSC line (LX2). BA trafficking/uptake were assessed extracellularly (LX2 culture medium) and intracellularly following treatment with/without NTCP neutralizing antibody. LF models of C57/BL6 mice of carbon tetrachloride (CCl(4)) and leptin-deficient (Ob/Ob) fed with high-fat diet (Ob/Ob (HFD) ) were evaluated for pHSCs-NTCP expressions, metabolic and LF profiles following intraperitoneal injections of NTCP neutralizing antibody. RESULTS: pHSCs from F3/F4-scored patients of LF exhibit threefold increased NTCP expressions compared with F0-scored patients (p<0.0001). Sorted-activated HSCs (LX2(αSMA+)) showed high expressions of NTCP and high TCA uptake in vitro and triggered a further increase in their activations. This phenomenon was inhibited with NTCP small interfering RNA and the NTCP neutralizing antibody. Sorted LX2(NTCP+) (high alpha smooth muscle actin (αSMA)/high NTCP) cells showed high phosphorylated pathways of AKT/mTOR and protein kinase C (PKC) accompanied with a decrease in farnesoid X receptor expression. Moreover, LX2(NTCP+) cells treated with EGCG, OCA and PKC inhibitor HA-100 significantly decreased NTCP and αSMA. NTCP neutralizing antibody inhibited NTCP (less TCA uptake); it attenuated LF in both CCl(4) and Ob/Ob (HFD) animal models with ameliorated metabolic profile. CONCLUSION: NTCP expression is linearly correlated with fibrosis severity. Modulated BA trafficking could be an important step in LF pathogenesis. Antagonising BA uptake may suggest a therapeutic strategy for preventing disease progression. BMJ Publishing Group 2022-07 2021-07-15 /pmc/articles/PMC9185811/ /pubmed/34266968 http://dx.doi.org/10.1136/gutjnl-2020-323345 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Hepatology
Salhab, Ahmad
Amer, Johnny
Lu, Yinying
Safadi, Rifaat
Sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis
title Sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis
title_full Sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis
title_fullStr Sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis
title_full_unstemmed Sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis
title_short Sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis
title_sort sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis
topic Hepatology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9185811/
https://www.ncbi.nlm.nih.gov/pubmed/34266968
http://dx.doi.org/10.1136/gutjnl-2020-323345
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