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Characterization of the properties of a selective, orally bioavailable autotaxin inhibitor in preclinical models of advanced stages of liver fibrosis
Author(s) -
Baader Manuel,
Bretschneider Tom,
Broermann Andre,
Rippmann Joerg F,
Stierstorfer Birgit,
Kuttruff Christian A,
Mark Michael
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14118
Subject(s) - autotaxin , lysophosphatidic acid , fibrosis , steatohepatitis , pharmacology , lysophosphatidylcholine , cirrhosis , cancer research , medicine , fatty liver , biology , receptor , biochemistry , phospholipid , disease , membrane , phosphatidylcholine
Background and Purpose Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non‐alcoholic steatohepatitis (NASH) remains unclear. Experimental Approach The relevance of ATX in the pathogenesis of liver fibrosis was investigated by oral administration of Ex_31, a selective ATX inhibitor, in a 10 week model of carbon tetrachloride‐induced liver injury and in a 14 week model of choline‐deficient amino acid‐defined diet‐induced liver injury in rats. Key Results Oral administration of Ex_31, a selective ATX inhibitor, at 15 mg·kg −1 twice daily in therapeutic intervention mode resulted in efficient ATX inhibition and more than 95% reduction in plasma LPA levels in both studies. Treatment with Ex_31 had no effect on biomarkers of liver function, inflammation, or fibrosis and did not result in histological improvements in diseased animals. Conclusions and Implications Our findings question the role of ATX in the pathogenesis of hepatic fibrosis and the potential of small molecule ATX inhibitors for the treatment of patients with NASH and advanced stages of liver fibrosis.