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Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis
Open AccessArticle

Combined Treatment with Sodium-Glucose Cotransporter-2 Inhibitor (Canagliflozin) and Dipeptidyl Peptidase-4 Inhibitor (Teneligliptin) Alleviates NASH Progression in A Non-Diabetic Rat Model of Steatohepatitis

Department of Gastroenterology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
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Int. J. Mol. Sci. 2020, 21(6), 2164; https://doi.org/10.3390/ijms21062164
Received: 11 February 2020 / Revised: 19 March 2020 / Accepted: 19 March 2020 / Published: 21 March 2020
(This article belongs to the Special Issue Diabetic Liver Disease)
Hepatocellular carcinoma (HCC) is the strongest independent predictor of mortality in non-alcoholic steatohepatitis (NASH)-related cirrhosis. The effects and mechanisms of combination of sodium-dependent glucose cotransporter inhibitor and canagliflozin (CA) and dipeptidyl peptidase-4 inhibitor and teneligliptin (TE) on non-diabetic NASH progression were examined. CA and TE suppressed choline-deficient, L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. CA alone or with TE significantly decreased proinflammatory cytokine expression. CA and TE significantly attenuated hepatic lipid peroxidation. In vitro studies showed that TE alone or with CA inhibited cell proliferation and TGF-β1 and α1 (I)-procollagen mRNA expression in Ac-HSCs. CA+TE inhibited liver fibrogenesis by attenuating hepatic lipid peroxidation and inflammation and by inhibiting Ac-HSC proliferation with concomitant attenuation of hepatic lipid peroxidation. Moreover, CA+TE suppressed in vivo angiogenesis and oxidative DNA damage. CA or CA+TE inhibited HCC cells and human umbilical vein endothelial cell (HUVEC) proliferation. CA+TE suppressed vascular endothelial growth factor expression and promoted increased E-cadherin expression in HUVECs. CA+TE potentially exerts synergistic effects on hepatocarcinogenesis prevention by suppressing HCC cell proliferation and angiogenesis and concomitantly reducing oxidative stress and by inhibiting angiogenesis with attenuation of oxidative stress. CA+TE showed chemopreventive effects on NASH progression compared with single agent in non-diabetic rat model of NASH, concurrent with Ac-HSC and HCC cell proliferation, angiogenesis oxidative stress, and inflammation. Both agents are widely, safely used in clinical practice; combined treatment may represent a potential strategy against NASH. View Full-Text
Keywords: non-alcoholic steatohepatitis; hepatic fibrogenesis; hepatocarcinogenesis; canagliflozin; teneligliptin non-alcoholic steatohepatitis; hepatic fibrogenesis; hepatocarcinogenesis; canagliflozin; teneligliptin
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MDPI and ACS Style

Ozutsumi, T.; Namisaki, T.; Shimozato, N.; Kaji, K.; Tsuji, Y.; Kaya, D.; Fujinaga, Y.; Furukawa, M.; Nakanishi, K.; Sato, S.; Sawada, Y.; Saikawa, S.; Kitagawa, K.; Takaya, H.; Kawaratani, H.; Kitade, M.; Moriya, K.; Noguchi, R.; Akahane, T.; Mitoro, A.; Yoshiji, H. Combined Treatment with Sodium-Glucose Cotransporter-2 Inhibitor (Canagliflozin) and Dipeptidyl Peptidase-4 Inhibitor (Teneligliptin) Alleviates NASH Progression in A Non-Diabetic Rat Model of Steatohepatitis. Int. J. Mol. Sci. 2020, 21, 2164. https://doi.org/10.3390/ijms21062164

AMA Style

Ozutsumi T, Namisaki T, Shimozato N, Kaji K, Tsuji Y, Kaya D, Fujinaga Y, Furukawa M, Nakanishi K, Sato S, Sawada Y, Saikawa S, Kitagawa K, Takaya H, Kawaratani H, Kitade M, Moriya K, Noguchi R, Akahane T, Mitoro A, Yoshiji H. Combined Treatment with Sodium-Glucose Cotransporter-2 Inhibitor (Canagliflozin) and Dipeptidyl Peptidase-4 Inhibitor (Teneligliptin) Alleviates NASH Progression in A Non-Diabetic Rat Model of Steatohepatitis. International Journal of Molecular Sciences. 2020; 21(6):2164. https://doi.org/10.3390/ijms21062164

Chicago/Turabian Style

Ozutsumi, Takahiro; Namisaki, Tadashi; Shimozato, Naotaka; Kaji, Kosuke; Tsuji, Yuki; Kaya, Daisuke; Fujinaga, Yukihisa; Furukawa, Masanori; Nakanishi, Keisuke; Sato, Shinya; Sawada, Yasuhiko; Saikawa, Soichiro; Kitagawa, Koh; Takaya, Hiroaki; Kawaratani, Hideto; Kitade, Mitsuteru; Moriya, Kei; Noguchi, Ryuichi; Akahane, Takemi; Mitoro, Akira; Yoshiji, Hitoshi. 2020. "Combined Treatment with Sodium-Glucose Cotransporter-2 Inhibitor (Canagliflozin) and Dipeptidyl Peptidase-4 Inhibitor (Teneligliptin) Alleviates NASH Progression in A Non-Diabetic Rat Model of Steatohepatitis" Int. J. Mol. Sci. 21, no. 6: 2164. https://doi.org/10.3390/ijms21062164

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