TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats.
Daisuke KayaKosuke KajiYuki TsujiSatoko YamashitaKoh KitagawaTakahiro OzutsumiYukihisa FujinagaHiroaki TakayaHideto KawarataniKei MoriyaTadashi NamisakiTakemi AkahaneHitoshi YoshijiPublished in: Cells (2019)
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.
Keyphrases
- liver fibrosis
- diabetic rats
- oxidative stress
- induced apoptosis
- type diabetes
- cell cycle arrest
- signaling pathway
- glycemic control
- insulin resistance
- knee osteoarthritis
- cell death
- metabolic syndrome
- high fat diet
- cell proliferation
- combination therapy
- adipose tissue
- fatty acid
- human health
- amino acid
- weight loss
- endothelial cells
- high glucose
- high fat diet induced