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TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats
Daisuke Kaya1, Kosuke Kaji2, Yuki Tsuji3
1Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan. kayad@naramed-u.ac.jp.
Abstract:
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.
Insights
Combining a Takeda G protein-coupled receptor 5 (TGR5) agonist and a dipeptidyl peptidase-4 (DPP-4) inhibitor shows promise for treating liver fibrosis in diabetic conditions. This novel strategy effectively reduces liver damage and improves metabolic health.
Area of Science:
- Hepatology
- Endocrinology
- Pharmacology
Background:
- Hyperglycemia and hyperinsulinemia exacerbate liver fibrosis by activating hepatic stellate cells (HSCs).
- Dipeptidyl peptidase-4 (DPP-4) inhibitors and Takeda G protein-coupled receptor 5 (TGR5) agonists are known to modulate glucose metabolism and potentially inhibit HSC proliferation.
Purpose of the Study:
- To investigate the combined efficacy of a TGR5 agonist and a DPP-4 inhibitor in mitigating liver fibrosis associated with diabetes.
- To evaluate the impact of these agents on glycemic control, intrahepatic steatosis, and HSC activity.
Main Methods:
- Diabetic rats were induced with liver fibrosis using porcine serum (PS) and treated with oleanolic acid (OA, TGR5 agonist), anagliptin (ANA, DPP-4 inhibitor), or a combination.
- Assessments included glycemic status, intrahepatic steatosis, lipid peroxidation, liver fibrosis markers, fecal microbiome composition, and in vitro HSC activity.
Main Results:
- Both OA and ANA treatments significantly improved glycemic control, reduced steatosis and lipid peroxidation, and suppressed liver fibrosis.
- The combination therapy demonstrated enhanced antifibrotic effects compared to individual treatments.
- Both agents normalized the Firmicutes/Bacteroidetes ratio in the gut microbiome, and ANA directly inhibited HSC proliferation and profibrogenic actions in vitro.
Conclusions:
- The combination of a TGR5 agonist and a DPP-4 inhibitor presents a potent, novel therapeutic strategy for combating liver fibrosis in diabetic patients.
- This approach targets both glycemic dysregulation and fibrotic pathways, offering a dual benefit for liver health.
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