RESUMO
BACKGROUND/OBJECTIVES: Effects of norursodeoxycholic acid (norUDCA) and ursodeoxycholic acid (UDCA) on liver fibrosis progression and liver fibrosis reversal in thioacetamide (TAA)-treated rats were studied. METHODS: Advanced liver fibrosis was induced by TAA treatment (200 mg/kg, i.p.) for 12 weeks. In the second experiment resolution of liver fibrosis was assessed after 8 weeks of TAA withdrawal. During 8 last weeks of each trial, fibrotic rats were daily administered with UDCA (80 mg/kg) and norUDCA (equimolar to 80 mg/kg of UDCA) by oral gavage. Liver fibrosis was assessed by Sirius red staining, liver hydroxyproline and serum fibrosis markers determination. RESULTS: The TAA treatment resulted in advanced fibrosis and increase in liver hydroxyproline content and serum fibrosis markers. These signs of fibrosis were less pronounced in rats after TAA withdrawal. Treatment with of norUDCA significantly decreased the total and relative liver hydroxyproline contents in rats with fibrosis reversal, whereas UDCA did not change these parameters. Both compounds decreased serum TGFß and type IV collagen contents, whereas other serum markers did not differ from the placebo group. In the fibrosis progression model the square of connective tissue was decreased by norUDCA. Serum type IV collagen and procollagen III-NT contents in these experiments were lowered by both UDCA and norUDCA, whereas rest of serum fibrosis markers were diminished only by norUDCA. CONCLUSIONS: Both norUDCA and UDCA showed therapeutic and prophylactic antifibrotic effect in rats with TAA-induced liver fibrosis. For most of tested parameters norUDCA was more effective than UDCA, especially in the experiment with liver fibrosis regression.
RESUMO
AIM: The data on the beneficial effect of ursodeoxycholic acid (UDCA) in non-alcoholic steatohepatitis (NASH) are controversial. The difference of opinion is connected with UDCA dosage to be used. Therefore, we evaluated the dose-dependent efficacy of UDCA in experimental NASH. METHODS: Male Wistar rats were fed the methionine- and choline-deficient (MCD) diet for 10 weeks. Rats were administrated UDCA (10, 20, 40 and 80 mg/kg bodyweight intragastrically) after 6 weeks of the MCD diet. RESULTS: Animals fed the MCD diet developed severe steatohepatitis. Treatment with UDCA dose-dependently decreased liver damage, but only high-dose UDCA (80 mg/kg) significantly diminished ultrastructural changes in addition to preventing steatosis, ballooning and inflammatory changes in the liver. The activities of serum marker enzymes and the content of liver triglyceride and blood glucose were increased in MCD diet-fed rats, but decreased in all the UDCA-treated groups. Serum insulin concentration was decreased whereas the quantitative insulin sensitivity check index did not changed in MCD diet-fed groups. Serum tumor necrosis factor-α content was strongly increased after MCD diet and normalized in the UDCA-treated rats, with the most pronounced effect in the highest dose groups, 40 and 80 mg/kg. The contents of endogenous ethanol in blood and intestinal mucus were increased in MCD diet-fed rats which were significantly lowered by UDCA (40 and 80 mg/kg per day). CONCLUSION: The present data demonstrate a beneficial effect of UDCA that manifested by the decrease of liver steatosis, inflammatory signs and serum tumor necrosis factor-α content especially of the highest 40 and 80 mg/kg day doses.