A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis

Abstract

The lysophosphatidic acid (LPA) signaling axis is an important but rather underexplored pathway in liver disease. LPA is predominantly produced by Autotaxin (ATX) that has gained significant attention with an impressive number of ATX inhibitors (type I-IV) reported. Here, we evaluated the therapeutic potential of a (yet unexplored) type IV inhibitor, Cpd17, in liver injury. We first confirmed the involvement of the ATX-LPA signaling axis in human and murine diseased livers. Then, we evaluated the effects of Cpd17, in comparison with the classic type I inhibitor PF8380, in vitro, where Cpd17 showed higher efficacy. Thereafter, we characterized the mechanism-of-action of both inhibitors and found that Cpd17 was more potent in inhibiting RhoA-mediated cytoskeletal remodeling, and phosphorylation of MAPK/ERK and AKT/PKB. Finally, the therapeutic potential of Cpd17 was investigated in CCl 4 -induced acute liver injury and diet-induced nonalcoholic steatohepatitis, demonstrating an excellent potential of Cpd17 in reducing liver injury in both disease models in vivo. We conclude that ATX inhibition, by type IV inhibitor in particular, has an excellent potential for clinical application in liver diseases.

ENPP2/Autotaxin: The potential drug target for alcoholic liver disease identified through Mendelian randomization analysis

“…Autotaxin inhibitors reduce steatosis in hepatocytes and migration and expression of inflammation-related genes in macrophages. 27 Also, Autotaxin was reported to modulate the innate immune response in acute liver failure via lysophosphatidylcholinic acid receptors 1 and 3 in peripheral monocytes. 28 This relationship and the mechanisms involved need to be confirmed by further studies.…”

“…30 The type IV inhibitor Cpd17 ameliorates acute liver injury and nonalcoholic steatohepatitis. 27 However, no studies with ALD models have been reported. Further preclinical studies should be performed in the future.…”

TRIB1 regulates liver regeneration by antagonizing the NRF2-mediated antioxidant response

“…Whole-cell lysates were obtained by re-suspending cell pellets in RIPA buffer (50 mM Tris pH7.4, 150 mM NaCl, 1% Triton X-100) with freshly added protease inhibitor (Roche) as previously described [ 45 , 46 ]. Nuclear proteins were prepared with the NE-PER Kit (Pierce) following the manufacturer’s recommendation.…”

Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease

“… 114 , 115 Inhibition of the major lysophosphatidic acid generating enzyme autotaxin (ectonucleotide pyrophosphatase/phosphodiesterase family member 2) using a selective inhibitor leads to significant improvement in fibrosis development in mouse models of liver injury and NASH. 116 In addition, autotaxin levels are elevated in the serum of patients with NAFLD and patients with liver cirrhosis as compared with healthy individuals and correlate with the stage of fibrosis. 117 , 118 Consistently, in a model of CCl 4 -induced liver injury in rats, circulating levels of lysophosphatidic acid and autotaxin activity are increased and correlate with the extent of liver fibrosis as well.…”