Obeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model.

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.

• Authors: Beatrice Anfuso, Claudio Tiribelli, Luciano Adorini, Natalia Rosso
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 1699 (02 03 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32015483 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6-ethyl-24-norcholane-3,7,23-triol-23 sulfate
• Benzamides
• Benzothiazoles
• Bile Acids and Salts
• FXR1 protein, human
• Fatty Acids, Nonesterified
• Imidazoles
• Isoxazoles
• Protein Kinase Inhibitors
• Pyridines
• RNA-Binding Proteins
• Receptors, Cytoplasmic and Nuclear
• nuclear receptor subfamily 0, group B, member 2
• obeticholic acid
• Chenodeoxycholic Acid
• Collagen
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• tropifexor
• selonsertib

Topics

• Benzamides (pharmacology)
• Benzothiazoles (pharmacology)
• Bile Acids and Salts (pharmacology)
• Cell Line
• Chenodeoxycholic Acid (analogs & derivatives, metabolism)
• Coculture Techniques
• Collagen (metabolism)
• Fatty Acids, Nonesterified (metabolism)
• Hepatic Stellate Cells (metabolism, pathology)
• Hepatocytes (physiology)
• Humans
• Imidazoles (pharmacology)
• Isoxazoles (pharmacology)
• Liver (metabolism, pathology)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Non-alcoholic Fatty Liver Disease (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• RNA-Binding Proteins (agonists)
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)