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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal
Open Access

The GPR40 Full Agonist SCO-267 Improves Liver Parameters in a Mouse Model of Nonalcoholic Fatty Liver Disease without Affecting Glucose or Body Weight

Mitsugi Ookawara, Keisuke Matsuda, Masanori Watanabe and Yusuke Moritoh
Journal of Pharmacology and Experimental Therapeutics October 2020, 375 (1) 21-27; DOI: https://doi.org/10.1124/jpet.120.000046
Mitsugi Ookawara
SCOHIA PHARMA, Inc., Kanagawa, Japan
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Keisuke Matsuda
SCOHIA PHARMA, Inc., Kanagawa, Japan
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Masanori Watanabe
SCOHIA PHARMA, Inc., Kanagawa, Japan
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Yusuke Moritoh
SCOHIA PHARMA, Inc., Kanagawa, Japan
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    Fig. 1.

    Effects of SCO-267 on glucagon and GLP-1 secretion in CDAHFD-fed mice. (A) Glucagon levels and (B) GLP-1 levels after drug dosing. SCO-267–stimulated glucagon and GLP-1 secretion in CDAHFD-fed mice. Values are presented as means ± S.D. (n = 5). †P < 0.025 and ‡P < 0.025 vs. vehicle by one-tailed Williams’ test and one-tailed Shirley-Williams test, respectively. AUC0–2 h, area under the curve from 0 to 2 hours; SCO, SCO-267; Veh, vehicle.

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    Fig. 2.

    Effects of repeated doses of SCO-267 on metabolic parameters in CDAHFD-fed mice. (A) Daily food intake, (B) change in body weight during the study, (C) plasma glucose, and (D) plasma triglyceride at the end of the 4-week study. Baseline body weight for CDAHFD group was 25.4 ± 1.6 g. SCO-267 did not affect food intake, body weight, plasma glucose, or plasma triglyceride levels. Values are presented as means ± S.D. (n = 8). *P < 0.05 vs. vehicle by Student’s t test. Alo, alogliptin benzoate; Dapa, dapagliflozin; SCO, SCO-267; SD, standard diet; Veh, vehicle.

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    Fig. 3.

    Effects of repeated doses of SCO-267 on liver parameters in CDAHFD-fed mice. (A) Liver triglyceride content, (B) liver weight, (C) liver collagen content, and (D) plasma alanine aminotransferase levels at the end of the 4-week study. SCO-267 decreased liver triglyceride content, liver weight, liver collagen content, and plasma alanine aminotransferase levels. Values are presented as means ± S.D. (n = 8). †P < 0.025 vs. vehicle by one-tailed Williams’ test. Alo, alogliptin benzoate; Dapa, dapagliflozin; SCO, SCO-267; SD, standard diet; Veh, vehicle.

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    Fig. 4.

    Effects of repeated doses of SCO-267 on liver TBARS levels in CDAHFD-fed mice. Liver TBARS levels at the end of the 4-week study. SCO-267 decreased liver TBARS levels. Values are presented as means ± S.D. (n = 8). ‡P < 0.025 vs. vehicle by one-tailed Shirley-Williams test. Alo, alogliptin benzoate; Dapa, dapagliflozin; SCO, SCO-267; SD, standard diet; Veh, vehicle.

  • Fig. 5.
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    Fig. 5.

    Effects of repeated doses of SCO-267 on liver mRNA levels in CDAHFD-fed mice. Liver levels of mRNAs related to (A) mitochondrial function, (B) β-oxidation pathway, (C) lipogenesis pathway, (D) inflammation pathway, (E) reactive oxygen species generation, and (F) fibrosis pathway at the end of the 4-week study. SCO-267–elevated mRNA levels of molecules with roles in mitochondrial function and β-oxidation and inhibited those with roles in lipogenesis, inflammation, reactive oxygen species generation, and fibrosis in the liver. Values are presented as means ± S.D. (n = 7 to 8). †P < 0.025 and ‡P < 0.025 vs. vehicle by one-tailed Williams’ test and Shirley-Williams test, respectively. *P < 0.05 and **P < 0.01 vs. vehicle by Student’s t test. #P < 0.05 and ##P < 0.01 vs. vehicle by Aspin-Welch test. Acadl, acyl-CoA dehydrogenase, long chain; Acta2, actin, α2, smooth muscle, aorta; Alo, alogliptin benzoate; Ccl2, chemokine (C-C motif) ligand 2; Cd36, CD36 molecule; Col1a1, collagen type 1, α1; Cybb, cytochrome b-245, β polypeptide; Dapa, dapagliflozin; Il6, interleukin-6; Ncf1, neutrophil cytosol factor 1; Ppara, peroxisome proliferator–activated receptor α; SCO, SCO-267; SD, standard diet; Srebf1, sterol regulatory element binding transcription factor 1; Tfam, transcription factor A, mitochondrial; Tgfb1, transforming growth factor β 1; Tnf, tumor necrosis factor; Veh, vehicle.

Additional Files

  • Figures
  • Data Supplement

    • Supplemental Data -

      Supplementary Figure 1 - Pharmacokinetic analysis of CDAHFD-fed mice.

      Supplementary Figure 2 - Plasma insulin levels in CDAHFD-fed mice. 

      Supplementary Figure 3 - Plasma aspartate aminotransferase levels in CDAHFD-fed mice.

      Supplementary Figure 4 - Liver mRNA levels of G6pc and Gys2 in CDAHFD-fed mice.

      Supplementary Figure 5 - Liver mRNA levels of Ffar1.

      Supplementary Table 1 - Taqman Gene Expression Assays used for qPCR.

      Supplementary Table 2 - Primer sequences for SYBR green qPCR.

      Supplementary Table 3 - Primers, probe, and standard sequence for mouse Ffar1.

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Journal of Pharmacology and Experimental Therapeutics: 375 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 1
1 Oct 2020
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

GPR40 Full Agonist for Nonalcoholic Fatty Liver Disease

Mitsugi Ookawara, Keisuke Matsuda, Masanori Watanabe and Yusuke Moritoh
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 21-27; DOI: https://doi.org/10.1124/jpet.120.000046

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

GPR40 Full Agonist for Nonalcoholic Fatty Liver Disease

Mitsugi Ookawara, Keisuke Matsuda, Masanori Watanabe and Yusuke Moritoh
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 21-27; DOI: https://doi.org/10.1124/jpet.120.000046
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