TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats
by
Daisuke Kaya 1, Kosuke Kaji 1,*, Yuki Tsuji 1, Satoko Yamashita 2, Koh Kitagawa 1, Takahiro Ozutsumi 1, Yukihisa Fujinaga 1, Hiroaki Takaya 1, Hideto Kawaratani 1
, Kei Moriya 1, Tadashi Namisaki 1, Takemi Akahane 1 and Hitoshi Yoshiji 1
Daisuke Kaya 1, Kosuke Kaji 1,*, Yuki Tsuji 1, Satoko Yamashita 2, Koh Kitagawa 1, Takahiro Ozutsumi 1, Yukihisa Fujinaga 1, Hiroaki Takaya 1, Hideto Kawaratani 1, Kei Moriya 1, Tadashi Namisaki 1, Takemi Akahane 1 and Hitoshi Yoshiji 1
1
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
2
Sanwa Kagaku Kenkyusho, Co., Ltd., Nagoya, Aichi 461-8631, Japan
*
Author to whom correspondence should be addressed.
Cells 2019, 8(10), 1153; https://doi.org/10.3390/cells8101153
Received: 31 August 2019 / Revised: 21 September 2019 / Accepted: 24 September 2019 / Published: 26 September 2019
(This article belongs to the Special Issue Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis)
Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from intestinal L cells, which maintains glycemic homeostasis. This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities. Collectively, TGR5 agonist and DPP-4 inhibitor appears to be a novel strategy against liver fibrosis under diabetic conditions.
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Keywords:
dipeptidyl peptidase-4 inhibitors; hepatic stellate cells; oleanolic acid; Takeda G protein-coupled receptor 5
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MDPI and ACS Style
Kaya, D.; Kaji, K.; Tsuji, Y.; Yamashita, S.; Kitagawa, K.; Ozutsumi, T.; Fujinaga, Y.; Takaya, H.; Kawaratani, H.; Moriya, K.; Namisaki, T.; Akahane, T.; Yoshiji, H. TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats. Cells 2019, 8, 1153.
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