Dataset Information

LY2405319, an analog of fibroblast growth factor 21 ameliorates ?-smooth muscle actin production through inhibition of the succinate-G-protein couple receptor 91 (GPR91) pathway in mice.

ABSTRACT: Fibroblast growth factor 21 (FGF21) is an important metabolic regulator expressed predominantly in the liver. In this study, we evaluated the role of LY2405319, an analogue of FGF21, in hepatic stellate cell (HSC) activation and in a methionine and choline-deficient (MCD)-diet induced mouse model of liver fibrosis. During liver injury, HSCs trans-differentiate into activated myofibroblasts which produce alpha-smooth muscle actin (?-SMA) and become a major cell type in hepatic fibrogenesis. Succinate and succinate receptor (GPR91) signaling has emerged as a regulator to promote ?-SMA production in MCD diet- induced mice. Treatment with palmitate or MCD medium on LX-2 cells (HSCs) increased succinate concentration in the conditioned medium and cell lysate of LX-2 cells and increased production of GPR91 and ?-SMA. However, LY2405319 administration ameliorates palmitate or MCD media-induced succinate production and decreases over-expression of GPR91 and ?-SMA in LX2-cells. In an in vivo study, the MCD diet treatment caused increased steatohepatitis and liver fibrosis compared with the control diet in mice. Administration of LY2405319 improved steatohepatitis ameliorated GPR91 and ? -SMA production in the liver, decreased succinate concentration in both liver and serum of MCD diet -induced mice. These results suggest that FGF21 reduces production of ?-SMA by inhibiting the succinate-GPR91 pathway. We conclude that FGF21 acts as an inhibitor of the succinate-GPR91 pathway to control liver fibrosis. This suggests that FGF21 has therapeutic potential for treating liver fibrogenesis.

SUBMITTER: Le CT

PROVIDER: S-EPMC5812602 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

LY2405319, an analog of fibroblast growth factor 21 ameliorates α-smooth muscle actin production through inhibition of the succinate-G-protein couple receptor 91 (GPR91) pathway in mice.

Le Cong Thuc CT Nguyen Giang G Park So Young SY Choi Dae Hee DH Cho Eun-Hee EH

PloS one 20180214 2

Fibroblast growth factor 21 (FGF21) is an important metabolic regulator expressed predominantly in the liver. In this study, we evaluated the role of LY2405319, an analogue of FGF21, in hepatic stellate cell (HSC) activation and in a methionine and choline-deficient (MCD)-diet induced mouse model of liver fibrosis. During liver injury, HSCs trans-differentiate into activated myofibroblasts which produce alpha-smooth muscle actin (α-SMA) and become a major cell type in hepatic fibrogenesis. Succi ...[more]

PMID: 29444136

Similar Datasets

Project description:Infarcted myocardium is predisposed to cause lethal ventricular arrhythmias that remain the main cause of death in patients suffering myocardial ischemia. Liver-derived fibroblast growth factor 21 (FGF21) is an endocrine regulator, which exerts metabolic actions by favoring glucose and lipids metabolism. Emerging evidence has shown a beneficial effect of FGF21 on cardiovascular diseases, but the role of FGF21 on ventricular arrhythmias following myocardial infarction (MI) in humans has never been addressed. This study was conducted to investigate the pharmacological effects of FGF21 on cardiomyocytes after MI in humans. Patients with arrhythmia in acute MI and healthy volunteers were enrolled in this study. Serum samples were collected from these subjects on day 1 and days 7-10 after the onset of MI for measuring FGF21 levels using ELISA. Here, we found that the serum level of FGF21 was significantly increased on day 1 after the onset of MI and it returned to normal on days 7-10, relative to the Control samples. In order to clarify the regulation of FGF21 on arrhythmia, two kinds of arrhythmia animal models were established in this study, including ischemic arrhythmia model (MI rat model) and nonischemic arrhythmia model (ouabain-induced guinea pig arrhythmia model). The results showed that the incidence and duration time of ischemic arrhythmias in rhbFGF21-treated MI rats were significantly reduced at different time point after MI compared with normal saline-treated MI rats. Moreover, the onset of the first ventricular arrhythmias was delayed and the numbers of VF and maintenance were attenuated by FGF21 compared to the rhbFGF21-untreated group in the ouabain model. Consistently, in vitro study also demonstrated that FGF21 administration was able to shorten action potential duration (APD) in hydrogen peroxide-treated AC16 cells. Mechanically, FGF21 can ameliorate the electrophysiological function of AC16 cells, which is characterized by rescuing the expression and dysfunction of cardiac sodium current (I Na) and inward rectifier potassium (I k1) in AC16 cells induced by hydrogen peroxide. Moreover, the restorative effect of FGF21 on NaV1.5 and Kir2.1 was eliminated when FGF receptors were inhibited. Collectively, FGF21 has the potential role of ameliorating transmembrane ion channels remodeling through the NaV1.5/Kir2.1 pathway by FGF receptors and thus reducing life-threatening postinfarcted arrhythmias, which provides new strategies for antiarrhythmic therapy in clinics.

Dataset Information

LY2405319, an analog of fibroblast growth factor 21 ameliorates ?-smooth muscle actin production through inhibition of the succinate-G-protein couple receptor 91 (GPR91) pathway in mice.

Publications

LY2405319, an analog of fibroblast growth factor 21 ameliorates α-smooth muscle actin production through inhibition of the succinate-G-protein couple receptor 91 (GPR91) pathway in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets