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

Abstract

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.

• Authors: Shiho Kanai, Keiichi Ishihara, Eri Kawashita, Toshiyuki Tomoo, Kazuhiro Nagahira, Yasuhiro Hayashi, Satoshi Akiba
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 356 Issue 3 Pg. 604-14 (Mar 2016) ISSN: 1521-0103 [Electronic] United States
• PMID: 26699145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• 3-(1-(4-phenoxyphenyl)-3-(2-phenylethyl)-1H-indol-5-yl)propanoic acid
• Enzyme Inhibitors
• Indoles
• Phospholipase A2 Inhibitors
• Propionates
• Group IV Phospholipases A2

Topics

• Administration, Oral
• Animals
• Enzyme Inhibitors (administration & dosage)
• Group IV Phospholipases A2 (antagonists & inhibitors, metabolism)
• Indoles (administration & dosage)
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (drug therapy, enzymology)
• Phospholipase A2 Inhibitors (administration & dosage)
• Propionates (administration & dosage)