Hepatoprotective and antioxidant effects of caffeine and silymarin combination by decreasing lysophosphatidic acid receptor 3 tissue and gene expression in rats

Liver disease causes about 2 million deaths yearly in the world. Caffeine (Caff) is the most common psychoactive substance utilized around the world. Caff has been demonstrated to possess anti-fibrotic actions in the liver. Silymarin (Sily) is a natural product largely used for its hepatoprotective actions through antioxidant, anti-inflammatory, and anti-fibrotic effects. Aim of the study: The current study aims to investigate the hepatoprotective and antioxidant effects of Caff and Sily alone or in combination in a rat model of liver fibrosis focusing on their effects on lysophosphatidic acid receptor 3 (LPAR3) expression. Materials and methods: 200 mg/kg of thioacetamide (TAA) was injected intraperitoneally twice weekly for 8 weeks to induce liver fibrosis. Caff, Sily, and their combination were orally administered to rats at a dose of 50 mg/kg/day for 8 weeks together with TAA injection. Results: Caff and Sily alone or in combination significantly improved liver function tests compared with fibrotic group. Moreover, they significantly decreased hepatic malondialdehyde (MDA) content and significantly increased the hepatic glutathione (GSH) concentration as compared with the fibrotic group. They significantly decreased fibrosis and necro-inflammatory scores with a superior significant effect in the necro-inflammatory score for the combination group each drug alone. Caff and Sily alone or in combination significantly decreased the hepatic LPAR3 gene and tissue expression, which was significantly correlated to their hepatoprotective effects. Conclusion: Caff and Sily alone or in combination protected against hepatic fibrosis through down-regulation of LPAR3 as well as antioxidant effects.