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Article

Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112)

1
Eisai Product Creation Systems, KAN Product Creation Unit, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan
2
KAN Research Institute, Inc., 6-8-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo 6500047, Japan
3
Medicine Creation, Neurology Business Group, Translational Medicine Department, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Eiichi Gohda
Int. J. Mol. Sci. 2021, 22(9), 4578; https://doi.org/10.3390/ijms22094578
Received: 20 March 2021 / Revised: 22 April 2021 / Accepted: 22 April 2021 / Published: 27 April 2021
(This article belongs to the Special Issue Hepatocyte Growth Factor (HGF), II)
Background: Hepatocyte growth factor (HGF) is an endogenously induced bioactive molecule that has strong anti-apoptotic and tissue repair activities. In this research, we identified APOA4 as a novel pharmacodynamic (PD) marker of the recombinant human HGF (rh-HGF), E3112. Methods: rh-HGF was administered to mice, and their livers were investigated for the PD marker. Candidates were identified from soluble proteins and validated by using human hepatocytes in vitro and an animal disease model in vivo, in which its c-Met dependency was also ensured. Results: Among the genes induced or highly enhanced after rh-HGF exposure in vivo, a soluble apolipoprotein, Apoa4, was found to be induced by rh-HGF in the murine liver. By using primary cultured human hepatocytes, the significant induction of human APOA4 was observed at the mRNA and protein levels, and it was inhibited in the presence of a c-Met inhibitor. Although mice constitutively expressed Apoa4 mRNA in the small intestine and the liver, the liver was the primary organ affected by administered rh-HGF to strongly induce APOA4 in a dose- and c-Met-dependent manner. Serum APOA4 levels were increased after rh-HGF administration, not only in normal mice but also in anti-Fas-induced murine acute liver failure (ALF), which confirmed the pharmacodynamic nature of APOA4. Conclusions: APOA4 was identified as a soluble PD marker of rh-HGF with c-Met dependency. It should be worthwhile to clinically validate its utility through clinical trials with healthy subjects and ALF patients. View Full-Text
Keywords: rh-HGF; APOA4; ALF; c-Met; Fas rh-HGF; APOA4; ALF; c-Met; Fas
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MDPI and ACS Style

Motoi, S.; Uesugi, M.; Obara, T.; Moriya, K.; Arita, Y.; Ogasawara, H.; Soejima, M.; Imai, T.; Kawano, T. Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112). Int. J. Mol. Sci. 2021, 22, 4578. https://doi.org/10.3390/ijms22094578

AMA Style

Motoi S, Uesugi M, Obara T, Moriya K, Arita Y, Ogasawara H, Soejima M, Imai T, Kawano T. Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112). International Journal of Molecular Sciences. 2021; 22(9):4578. https://doi.org/10.3390/ijms22094578

Chicago/Turabian Style

Motoi, Sotaro, Mai Uesugi, Takashi Obara, Katsuhiro Moriya, Yoshihisa Arita, Hideaki Ogasawara, Motohiro Soejima, Toshio Imai, and Tetsu Kawano. 2021. "Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112)" International Journal of Molecular Sciences 22, no. 9: 4578. https://doi.org/10.3390/ijms22094578

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