Regulation of Plasma Membrane Localization of the Na+-Taurocholate Co-Transporting Polypeptide by Glycochenodeoxycholate and Tauroursodeoxycholate

Mayer, P; Qvartskhava, Natalia; Sommerfeld, Annika; Görg, Boris; Häussinger, Dieter

doi:10.33594/000000100

Cited by 7 publications

(4 citation statements)

References 61 publications

(108 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This post-translational regulation is mediated via signalling pathways involving cyclic AMP, calcium, nitric oxide, phosphoinositide 3-kinase, PKC and protein phosphatases. 6 5. NTCP neutralizing antibody.…”

Section: Discussionmentioning

confidence: 99%

“…5 Signalling pathways involving cyclic AMP, calcium, nitric oxide, phosphoinositide 3-kinase, protein kinase C (PKC) and protein phosphatases mediate this post-translational regulation. 6 NTCP expression is diminished in cholestasis people and animal models of cholestasis induced by biliary obstruction, oestrogen or endotoxin. 7 A key NTCP repressive mechanism involves activation of the farnesoid X receptor (FXR) through accumulation of BAs, thus inducing the small heterodimer partner (SHP), a repressor of hepatic nuclear factor 1 (HNF 1) and HNF4α, and also interfering with retinoid X receptor-retinoic acid receptor heterodimers in rats or the glucocorticoid receptor in humans, all of which are required for normal NTCP expression.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Salhab

Amer

et al. 2021

Gut

View full text Add to dashboard Cite

ObjectiveSodium+/ 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).DesignPrimary 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 (CCl4) 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.ResultspHSCs from F3/F4-scored patients of LF exhibit threefold increased NTCP expressions compared with F0-scored patients (p<0.0001). Sorted-activated HSCs (LX2αSMA+) 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 LX2NTCP+ (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, LX2NTCP+ 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 CCl4 and Ob/Ob HFD animal models with ameliorated metabolic profile.ConclusionNTCP 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Salhab

Amer

et al. 2021

Gut

View full text Add to dashboard Cite

show abstract

“…Importantly, β 2 -adrenoreceptor antagonists, but not α-adrenoreceptor antagonists, suppressed the epinephrine-mediated repression of the BA transporters ( Mayati et al , 2017 ), which indicates a β-adrenoreceptor-cAMP-dependent effect. These results are in contrast, however, with the inducing effect of cAMP, an important second messenger released following β-adrenoreceptor stimulation, on BA biliary secretion by stabilizing BA transporters at the canalicular and basolateral membranes ( Mayer et al , 2019 ). Carvedilol has not been studied in this context yet.…”

mentioning

confidence: 93%

Carvedilol impairs bile acid homeostasis in mice: implication for nonalcoholic steatohepatitis

Lastuvkova,

Nova,

Hroch

et al. 2023

Toxicological Sciences

View full text Add to dashboard Cite

Carvedilol is a widely used beta-adrenoreceptor antagonist for multiple cardiovascular indications; however, it may induce cholestasis in patients, but the mechanism for this effect is unclear. Carvedilol also prevents the development of various forms of experimental liver injury, but its effect on nonalcoholic steatohepatitis (NASH) is largely unknown. In this study, we determined the effect of carvedilol (10 mg/kg/day p.o.) on bile formation and bile acid (BA) turnover in male C57BL/6 mice consuming either a chow diet or a western-type NASH-inducing diet. BAs were profiled by LC-MS and BA-related enzymes, transporters, and regulators were evaluated by western blot analysis and qRT-PCR. In chow diet-fed mice, carvedilol increased plasma concentrations of BAs resulting from reduced BA uptake to hepatocytes via Ntcp transporter downregulation. Inhibition of the β-adrenoreceptor-cAMP-Epac1-Ntcp pathway by carvedilol may be the post-transcriptional mechanism underlying this effect. In contrast, carvedilol did not worsen the deterioration of BA homeostasis accompanying NASH; however, it shifted the spectra of BAs toward more hydrophilic and less toxic α-muricholic and hyocholic acids. This positive effect of carvedilol was associated with a significant attenuation of liver steatosis, inflammation, and fibrosis in NASH mice. In conclusion, our results indicate that carvedilol may increase BAs in plasma by modifying their liver transport. In addition, carvedilol provided significant hepatoprotection in a NASH murine model without worsening BA accumulation. These data suggest beneficial effects of carvedilol in patients at high risk for developing NASH.

show abstract

Molecular regulation of the hepatic bile acid uptake transporter and HBV entry receptor NTCP

Appelman

Wettengel

Protzer

et al. 2021

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

View full text Add to dashboard Cite

Regulation of Plasma Membrane Localization of the Na+-Taurocholate Co-Transporting Polypeptide by Glycochenodeoxycholate and Tauroursodeoxycholate

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 7 publications

References 61 publications

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

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

Carvedilol impairs bile acid homeostasis in mice: implication for nonalcoholic steatohepatitis

Molecular regulation of the hepatic bile acid uptake transporter and HBV entry receptor NTCP

Contact Info

Product

Resources

About

Regulation of Plasma Membrane Localization of the Na+-Taurocholate Co-Transporting Polypeptide by Glycochenodeoxycholate and Tauroursodeoxycholate

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 7 publications

References 61 publications

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

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

Carvedilol impairs bile acid homeostasis in mice: implication for nonalcoholic steatohepatitis

Molecular regulation of the hepatic bile acid uptake transporter and HBV entry receptor NTCP

Contact Info

Product

Resources

About

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

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