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

Area of Science:

• Hepatology and Gastroenterology
• Molecular Biology
• Cellular Biology

Background:

• The sodium-taurocholate cotransporting polypeptide (NTCP) is a key transporter in bile acid (BA) enterohepatic circulation.
• Altered BA metabolism is implicated in the pathogenesis of liver fibrosis (LF).
• Understanding NTCP's role in LF is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of NTCP in human liver fibrosis.
• To evaluate the therapeutic potential of targeting NTCP in animal models of liver fibrosis.

Main Methods:

• NTCP expression was analyzed in human hepatic stellate cells (HSCs) from liver biopsies with varying fibrosis grades.
• In vitro studies modulated NTCP expression in LX2 cells using gene silencing, taurocholic acid (TCA), obeticholic acid (OCA), epigallocatechin gallate (EGCG), and HA-100.
• In vivo studies utilized carbon tetrachloride (CCl4) and leptin-deficient (Ob/Ob) mouse models of liver fibrosis, treated with an NTCP neutralizing antibody.

Main Results:

• NTCP expression was significantly higher in advanced stages of human liver fibrosis (F3/F4) compared to early stages (F0).
• Activated HSCs (LX2αSMA+) exhibited high NTCP expression and increased TCA uptake, promoting further activation, which was reversed by NTCP inhibition.
• NTCP inhibition in animal models attenuated liver fibrosis and improved metabolic profiles.

Conclusions:

• NTCP expression is directly correlated with liver fibrosis severity.
• Modulating bile acid uptake via NTCP antagonism presents a promising therapeutic strategy for liver fibrosis progression.