ASB14780, an Orally Active Inhibitor of Group IVA Phospholipase A2, Is a Pharmacotherapeutic Candidate for Nonalcoholic Fatty Liver Disease

• Published in: The Journal of pharmacology and experimental therapeutics 2016-03, Vol.356 (3), p.604-614
• Main Authors: Kanai, Shiho, Ishihara, Keiichi, Kawashita, Eri, Tomoo, Toshiyuki, Nagahira, Kazuhiro, Hayashi, Yasuhiro, Akiba, Satoshi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Enzyme Inhibitors - administration & dosage; Group IV Phospholipases A2 - antagonists & inhibitors; Group IV Phospholipases A2 - metabolism; Indoles - administration & dosage; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - enzymology; Phospholipase A2 Inhibitors - administration & dosage; Propionates - administration & dosage
• ISSN: 1521-0103; 1521-0103
• DOI: 10.1124/jpet.115.229906

We have previously shown that high-fat cholesterol diet (HFCD)-induced fatty liver and carbon tetrachloride (CCl4)-induced hepatic fibrosis are reduced in mice deficient in group IVA phospholipase A2 (IVA-PLA2), which plays a role in inflammation. We herein demonstrate the beneficial effects of ASB14780 (3-[1-(4-phenoxyphenyl)-3-(2-phenylethyl)-1H-indol-5-yl]propanoic acid 2-amino-2-(hydroxymethyl)propane-1,3-diol salt), an orally active IVA-PLA2 inhibitor, on the development of fatty liver and hepatic fibrosis in mice. The daily coadministration of ASB14780 markedly ameliorated liver injury and hepatic fibrosis following 6 weeks of treatment with CCl4. ASB14780 markedly attenuated the CCl4-induced expression of smooth muscle α-actin (α-SMA) protein and the mRNA expression of collagen 1a2, α-SMA, and transforming growth factor-β1 in the liver, and inhibited the expression of monocyte/macrophage markers, CD11b and monocyte chemotactic protein-1, while preventing the recruitment of monocytes/macrophages to the liver. Importantly, ASB14780 also reduced the development of fibrosis even in matured hepatic fibrosis. Additionally, ASB14780 also reduced HFCD-induced lipid deposition not only in the liver, but also in already established fatty liver. Furthermore, treatment with ASB14780 suppressed the HFCD-induced expression of lipogenic mRNAs. The present findings suggest that an IVA-PLA2 inhibitor, such as ASB14780, could be useful for the treatment of nonalcoholic fatty liver diseases, including fatty liver and hepatic fibrosis.