Protective Effects of Norursodeoxycholic Acid Versus Ursodeoxycholic Acid on Thioacetamide-induced Rat Liver Fibrosis

Vyacheslav U Buko; Oxana Y Lukivskaya; Elena E Naruta; Elena B Belonovskaya; Horst-Dietmar Tauschel

doi:10.1016/j.jceh.2014.02.001

Protective Effects of Norursodeoxycholic Acid Versus Ursodeoxycholic Acid on Thioacetamide-induced Rat Liver Fibrosis

J Clin Exp Hepatol. 2014 Dec;4(4):293-301. doi: 10.1016/j.jceh.2014.02.001. Epub 2014 Feb 21.

Authors

Vyacheslav U Buko¹, Oxana Y Lukivskaya², Elena E Naruta², Elena B Belonovskaya², Horst-Dietmar Tauschel³

Affiliations

¹ Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, BLK-50, Grodno 230030, Belarus ; School of Medical Sciences, Krakowska Str. 9, 15-875 Bialystok, Poland.
² Division of Biochemical Pharmacology, Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, BLK-50, Grodno 230030, Belarus.
³ Dr. Falk Pharma GmbH, Leinenweberstrasse 5, Freiburg 79041, Germany.

Abstract

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 TGFβ 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.

Keywords: ALT, aminotransferase; ANOVA, analysis of variance; AST, aspartate aminotransferase; NorUDCA, norursodeoxycholic acid; SEM, standard error of the mean; TAA, thioacetamide; TIMP-1, tissue inhibitor of metalloproteinase-1; UDCA, ursodeoxycholic acid; fibrosis; liver; norursodeoxycholic acid; thioacetamide; ursodeoxycholic acid.