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Published on: September 29, 2015
Obeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model
Beatrice Anfuso1, Claudio Tiribelli1, Luciano Adorini2
1Fondazione Italiana Fegato, AREA Science Park Basovizza, SS14 km 163.5, 34149, Trieste, Italy.
Abstract:
Pharmacological treatments for non-alcoholic steatohepatitis (NASH) are still unsatisfactory. Fibrosis is the most significant predictor of mortality and many anti-fibrotic agents are under evaluation. Herein, we assessed in vitro the effects of the FXR agonist obeticholic acid (OCA) and the dual FXR/TGR5 agonist INT-767 in a well-established co-culture NASH model. Co-cultures of human hepatoma and hepatic stellate (HSCs) cells were exposed to free fatty acids (FFAs) alone or in combination with OCA or INT-767. mRNA expression of HSCs activation markers and FXR engagement were evaluated at 24, 96 and 144 hours. Collagen deposition and metalloproteinase 2 and 9 (MMP2-9) activity were compared to tropifexor and selonsertib. FFAs induced collagen deposition and MMP2-9 activity reduction. Co-treatment with OCA or INT-767 did not affect ACTA2 and COL1A1 expression, but significantly reduced FXR and induced SHP expression, as expected. OCA induced a dose-dependent reduction of collagen and induced MMP2-9 activity. Similarly, INT-767 induced collagen reduction at 96 h and a slight increase in MMP2-9. Tropifexor and Selonsertib were also effective in collagen reduction but showed no modulation of MMP2-9. All tested compounds reduced collagen deposition. OCA exerted a more potent and long-lasting effect, mainly related to modulation of collagen turn-over and MMP2-9 activity.
Insights
Obeticholic acid (OCA) and INT-767 show promise in reducing liver fibrosis in non-alcoholic steatohepatitis (NASH) models. OCA demonstrated a potent, long-lasting anti-fibrotic effect by modulating collagen turnover and metalloproteinase activity.
Area of Science:
- Hepatology and Pharmacology
- Fibrosis Research
- Drug Discovery for Liver Diseases
Background:
- Current pharmacological treatments for non-alcoholic steatohepatitis (NASH) are insufficient.
- Liver fibrosis is a critical predictor of mortality in NASH patients.
- Novel anti-fibrotic agents targeting liver pathways are under investigation.
Purpose of the Study:
- To evaluate the in vitro efficacy of obeticholic acid (OCA) and INT-767 in a co-culture NASH model.
- To assess the impact of these agents on collagen deposition and matrix metalloproteinase activity.
- To compare their anti-fibrotic effects with tropifexor and selonsertib.
Main Methods:
- Utilized a co-culture model of human hepatoma and hepatic stellate cells exposed to free fatty acids (FFAs).
- Administered OCA and INT-767, assessing mRNA expression of hepatic stellate cell activation markers and FXR engagement.
- Quantified collagen deposition and metalloproteinase 2 and 9 (MMP2-9) activity.
Main Results:
- Free fatty acids induced collagen deposition and reduced MMP2-9 activity.
- OCA and INT-767 significantly reduced collagen deposition and modulated MMP2-9 activity.
- OCA exhibited a potent and sustained reduction in collagen, linked to collagen turnover and MMP2-9 modulation.
Conclusions:
- Obeticholic acid and INT-767 demonstrate anti-fibrotic potential in a NASH co-culture model.
- OCA shows a more pronounced and enduring effect, primarily through regulating collagen turnover and MMP2-9.
- These findings support further investigation of FXR agonists in treating liver fibrosis.
