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.

Highlights

  • Liver fibrosis is a common feature of chronic liver injuries caused by a variety of etiologies (e.g., hepatitis B, hepatitis C, autoimmune disorders, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD)) [1,2,3]

  • We proposed a combined treatment with the Dipeptidyl peptidase-4 (DPP-4) inhibitor ANA and the Takeda G protein-coupled receptor 5 (TGR5) agonist oleanolic acid (OA)

  • Our results demonstrated that in diabetic Otsuka Long–Evans Tokushima fatty (OLETF) rats, the TGR5 agonist OA efficiently potentiated the antifibrotic activity of ANA against porcine serum (PS)-induced hepatic fibrogenesis

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Summary

Introduction

Liver fibrosis is a common feature of chronic liver injuries caused by a variety of etiologies (e.g., hepatitis B, hepatitis C, autoimmune disorders, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD)) [1,2,3]. Liver fibrosis is characterized by hepatic stellate cell (HSC). Activation and excessive accumulation in the extracellular matrix. The progression of liver fibrosis is often influenced by various pathological conditions. The diabetic conditions type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are crucial to aggravate fibrogenesis [4,5]. Several epidemiological studies revealed that IR represents an advanced fibrosis risk factor in patients with chronic hepatitis C [6,7]. T2DM and IR are known risk factors for progressive fibrosis in

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