Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.).
Departments of Anatomy and Cell Biology (Y.J.O., H.Y.K., M.H.L., W.Y.K., Y.H.Y.), Endocrinology Medicine (S.H.S.), and Rheumatology (S.Y.L.), Dong-A University College of Medicine, Busan, Republic of Korea; Gyeonggi Bio Center, Gyeonggi-do Business and Science Accelerator, Suwon, Republic of Korea (Y.C.); and Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea (T.-G.N.)
Mol Pharmacol. 2018 Dec;94(6):1401-1411. doi: 10.1124/mol.118.113217. Epub 2018 Oct 26.
Nonalcoholic fatty liver disease (NAFLD) is an increasingly studied condition that can progress to end-stage liver disease. Although NAFLD was first described in 1980, a complete understanding of the mechanism and causes of this disease is still lacking. Six-transmembrane protein of prostate 2 (STAMP2) plays a role in integrating inflammatory and nutritional signals with metabolism. Our previous study suggested that STAMP2 may be a suitable target for treating NAFLD. In the current study, we performed a focused drug-screening and found that cilostazol could be a potential STAMP2 enhancer. Thus, we examined whether cilostazol alleviates NAFLD through STAMP2. The in vivo and in vitro pharmacological efficacies of cilostazol on STAMP2 expression and lipid accumulation were analyzed in NAFLD mice induced by high-fat diet (HFD) and in HepG2 cell lines treated by oleic acid (OA), respectively. Cilostazol increased the expression of STAMP2 through transcriptional regulation in vivo and in vitro. Cilostazol also dampened the STAMP2 downregulation caused by the HFD and by OA in vivo and in vitro, respectively. Cilostazol activated AMP-activated protein kinase (AMPK) in vivo and in vitro, and AMPK functions upstream of STAMP2, and reversed downregulation of STAMP2 expression through AMPK in the NAFLD model. Cilostazol ameliorates hepatic steatosis by enhancing hepatic STAMP2 expression through AMPK. Enhancing STAMP2 expression with cilostazol represents a potential therapeutic avenue for treatment of NAFLD.
非酒精性脂肪性肝病 (NAFLD) 是一种越来越受到研究关注的疾病，它可以进展为终末期肝病。尽管 NAFLD 于 1980 年首次被描述，但人们对这种疾病的发病机制和病因仍知之甚少。前列腺 6 跨膜蛋白 2 (STAMP2) 在整合炎症和营养信号与代谢方面发挥作用。我们之前的研究表明，STAMP2 可能是治疗 NAFLD 的一个合适靶点。在本研究中，我们进行了靶向药物筛选，发现西洛他唑可能是一种潜在的 STAMP2 增强剂。因此，我们研究了西洛他唑是否通过 STAMP2 缓解 NAFLD。在高脂肪饮食 (HFD) 诱导的 NAFLD 小鼠和油酸 (OA) 处理的 HepG2 细胞系中，分析了西洛他唑对 STAMP2 表达和脂质积累的体内和体外药效。西洛他唑通过体内和体外的转录调控增加了 STAMP2 的表达。西洛他唑还分别减弱了 HFD 和 OA 引起的 STAMP2 下调。西洛他唑在体内和体外均激活了 AMP 激活的蛋白激酶 (AMPK)，而 AMPK 位于 STAMP2 的上游，通过 AMPK 在 NAFLD 模型中逆转了 STAMP2 表达的下调。西洛他唑通过增强 AMPK 增强肝脏 STAMP2 表达来改善肝脂肪变性。用西洛他唑增强 STAMP2 表达代表了治疗 NAFLD 的一种潜在治疗途径。
