Department of Pharmacology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland.
Department of Pathomorphology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531, Krakow, Poland.
Cardiovasc Drugs Ther. 2024 Aug;38(4):667-678. doi: 10.1007/s10557-023-07430-7. Epub 2023 Jan 27.
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.
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.
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).
Pharmacological stimulation of FFAR4 may represent a promising lead in the search for drugs that inhibit NAFLD.
非酒精性脂肪性肝病（NAFLD）是冠心病发展的独立危险因素。低水平炎症在动脉粥样硬化和 NAFLD 的发展中起着重要作用。游离脂肪酸受体 4（FFAR4/GPR120）参与炎症反应的调节，可能是治疗炎症性疾病的有前途的靶点。我们的目的是评估合成 FFAR4/GPR120 激动剂 TUG-891 对体内脂肪肝的作用。
采用apoE 小鼠高脂饮食（HFD）模型，用显微镜、生化、分子和蛋白质组学方法研究 TUG-891 对脂肪肝的作用。
TUG-891 抑制 apoE 小鼠肝脂肪变性的进展，组织学分析显示，TUG-891 降低了肝内 TG 的积累。这种作用与血浆 AST 水平的降低有关。TUG-891 降低了参与从头合成脂肪（Srebp-1c、Fasn 和 Scd1）的肝脏基因和蛋白的表达，并降低了与氧化和摄取相关的基因的表达（Acox1、Ehhadh、Cd36、Fabp1）。此外，TUG-891 改变了与葡萄糖代谢相关的选定因子的水平（降低了 Glut2、Pdk4 和 Pklr，增加了 G6pdx）。
FFAR4 的药物刺激可能是抑制非酒精性脂肪性肝病药物研究的一个有前途的先导。
