title: 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.affiliation: Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan (S.K., K.I., E.K., S.A.); and Asubio Pharma Co., Ltd., Chuo-ku, Kobe, Japan (T.T., K.N., Y.H.).
authors.forename: Shiho
authors.initials: S
authors.lastname: Kanai
authors.affiliation: Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan (S.K., K.I., E.K., S.A.); and Asubio Pharma Co., Ltd., Chuo-ku, Kobe, Japan (T.T., K.N., Y.H.).
authors.forename: Keiichi
authors.identifier: http://orcid.org/0000-0001-8748-7218
authors.initials: K
authors.lastname: Ishihara
authors.affiliation: Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan (S.K., K.I., E.K., S.A.); and Asubio Pharma Co., Ltd., Chuo-ku, Kobe, Japan (T.T., K.N., Y.H.).
authors.forename: Eri
authors.initials: E
authors.lastname: Kawashita
authors.affiliation: Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan (S.K., K.I., E.K., S.A.); and Asubio Pharma Co., Ltd., Chuo-ku, Kobe, Japan (T.T., K.N., Y.H.).
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tomoo
authors.affiliation: Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan (S.K., K.I., E.K., S.A.); and Asubio Pharma Co., Ltd., Chuo-ku, Kobe, Japan (T.T., K.N., Y.H.).
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagahira
authors.affiliation: Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan (S.K., K.I., E.K., S.A.); and Asubio Pharma Co., Ltd., Chuo-ku, Kobe, Japan (T.T., K.N., Y.H.).
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan (S.K., K.I., E.K., S.A.); and Asubio Pharma Co., Ltd., Chuo-ku, Kobe, Japan (T.T., K.N., Y.H.) akiba@mb.kyoto-phu.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akiba
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000201:enzymology; D064801:Phospholipase A2 Inhibitors / Q000008:administration & dosage*; D011422:Propionates / Q000008:administration & dosage*
chemical_list: C000593222:3-(1-(4-phenoxyphenyl)-3-(2-phenylethyl)-1H-indol-5-yl)propanoic acid; D004791:Enzyme Inhibitors; D007211:Indoles; D064801:Phospholipase A2 Inhibitors; D011422:Propionates; D054513:Group IV Phospholipases A2