The Influence of the FFAR4 Agonist TUG-891 on Liver Steatosis in ApoE-Knockout Mice,Cardiovascular Drugs and Therapy

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The Influence of the FFAR4 Agonist TUG-891 on Liver Steatosis in ApoE-Knockout Mice
Cardiovascular Drugs and Therapy ( IF 3.1 ) Pub Date : 2023-01-27 , DOI: 10.1007/s10557-023-07430-7
Anna Kiepura ₁ , Maciej Suski ₁ , Kamila Stachyra ₁ , Katarzyna Kuś ₁ , Klaudia Czepiel ₁ , Anna Wiśniewska ₁ , Magdalena Ulatowska-Białas ₂ , Rafał Olszanecki ₁

Affiliation

Background

Nonalcoholic fatty liver disease (NAFLD) constitutes an independent risk factor for the development of coronary heart disease. Low-grade inflammation has been shown to play an important role in the development of atherosclerosis and NAFLD. Free fatty acid receptor 4 (FFAR4/GPR120), which is involved in damping inflammatory reactions, may represent a promising target for the treatment of inflammatory diseases. Our objective was to evaluate the effect of TUG-891, the synthetic agonist of FFAR4/GPR120, on fatty liver in vivo.

Methods

The effect of TUG-891 on fatty liver was investigated in apoE^−/− mice fed a high-fat diet (HFD), using microscopic, biochemical, molecular, and proteomic methods.

Results

Treatment with TUG-891 inhibited the progression of liver steatosis in apoE^−/− mice, as evidenced by histological analysis, and reduced the accumulation of TG in the liver. This action was associated with a decrease in plasma AST levels. TUG-891 decreased the expression of liver genes and proteins involved in de novo lipogenesis (Srebp-1c, Fasn and Scd1) and decreased the expression of genes related to oxidation and uptake (Acox1, Ehhadh, Cd36, Fabp1). Furthermore, TUG-891 modified the levels of selected factors related to glucose metabolism (decreased Glut2, Pdk4 and Pklr, and increased G6pdx).

Conclusion

Pharmacological stimulation of FFAR4 may represent a promising lead in the search for drugs that inhibit NAFLD.

Graphical abstract

中文翻译：

FFAR4 激动剂 TUG-891 对 ApoE 敲除小鼠肝脏脂肪变性的影响

背景

非酒精性脂肪肝（NAFLD）是冠心病发生的独立危险因素。低度炎症已被证明在动脉粥样硬化和 NAFLD 的发展中发挥重要作用。游离脂肪酸受体 4 (FFAR4/GPR120) 参与抑制炎症反应，可能是治疗炎症性疾病的一个有希望的靶点。我们的目的是评估 FFAR4/GPR120 的合成激动剂 TUG-891 对体内脂肪肝的作用。

方法

使用显微镜、生化、分子和蛋白质组学方法，在喂食高脂肪饮食 (HFD) 的 apoE ^−/−小鼠中研究 TUG-891 对脂肪肝的影响。

结果

组织学分析证明，TUG-891 治疗可抑制 apoE ^−/−小鼠肝脏脂肪变性的进展，并减少肝脏中 TG 的积累。这种作用与血浆 AST 水平的降低有关。 TUG-891 降低了参与从头脂肪生成的肝脏基因和蛋白质（Srebp-1c、Fasn 和 Scd1）的表达，并降低了与氧化和摄取相关的基因（Acox1、Ehhadh、Cd36、Fabp1）的表达。此外，TUG-891 改变了与葡萄糖代谢相关的选定因子的水平（降低 Glut2、Pdk4 和 Pklr，并增加 G6pdx）。