Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan 49201, Republic of Korea.
Department of Gastroenterology, Dong-A University College of Medicine, Busan 49201, Republic of Korea.
Int J Mol Sci. 2023 Aug 16;24(16):12862. doi: 10.3390/ijms241612862.
Hepatic iron overload (HIO) is a hallmark of nonalcoholic fatty liver disease (NAFLD) with a poor prognosis. Recently, the role of hepatic erythrophagocytosis in NAFLD is emerging as a cause of HIO. We undertook various assays using human NAFLD patient pathology samples and an in vivo nonalcoholic steatohepatitis (NASH) mouse model named STAM. To make the in vitro conditions comparable to those of the in vivo NASH model, red blood cells (RBCs) and platelets were suspended and subjected to metabolic and inflammatory stresses. An insert-coculture system, in which activated THP-1 cells and RBCs are separated from HepG2 cells by a porous membrane, was also employed. Through various analyses in this study, the effect of cilostazol was examined. The NAFLD activity score, including steatosis, ballooning degeneration, inflammation, and fibrosis, was increased in STAM mice. Importantly, hemolysis occurred in the serum of STAM mice. Although cilostazol did not improve lipid or glucose profiles, it ameliorated hepatic steatosis and inflammation in STAM mice. Platelets (PLTs) played an important role in increasing erythrophagocytosis in the NASH liver. Upregulated erythrophagocytosis drives cells into ferroptosis, resulting in liver cell death. Cilostazol inhibited the augmentation of PLT and RBC accumulation. Cilostazol prevented the PLT-induced increase in ectopic erythrophagocytosis in in vivo and in vitro NASH models. Cilostazol attenuated ferroptosis of hepatocytes and phagocytosis of RBCs by THP-1 cells. Augmentation of hepatic erythrophagocytosis by activated platelets in NASH exacerbates HIO. Cilostazol prevents ectopic erythrophagocytosis, mitigating HIO-mediated ferroptosis in NASH models.
肝铁过载 (HIO) 是非酒精性脂肪性肝病 (NAFLD) 的标志，预后不良。最近，肝红细胞吞噬作用在 NAFLD 中的作用作为 HIO 的一个原因正在出现。我们使用人类 NAFLD 患者病理样本和一种名为 STAM 的体内非酒精性脂肪性肝炎 (NASH) 小鼠模型进行了各种测定。为了使体外条件与体内 NASH 模型相媲美，悬浮红细胞 (RBC) 和血小板并对其进行代谢和炎症应激。还采用了一种插入共培养系统，其中激活的 THP-1 细胞和 RBC 通过多孔膜与 HepG2 细胞分离。通过本研究中的各种分析，检查了西洛他唑的作用。STAM 小鼠的 NAFLD 活性评分包括脂肪变性、气球样变性、炎症和纤维化均增加。重要的是，STAM 小鼠的血清中发生溶血。虽然西洛他唑没有改善脂质或葡萄糖谱，但它改善了 STAM 小鼠的肝脂肪变性和炎症。血小板 (PLT) 在增加 NASH 肝脏中的红细胞吞噬作用方面发挥了重要作用。上调的红细胞吞噬作用导致细胞发生铁死亡，从而导致肝细胞死亡。西洛他唑抑制了 PLT 和 RBC 积累的增加。西洛他唑防止了 PLT 在体内和体外 NASH 模型中诱导的异位红细胞吞噬作用增加。西洛他唑减弱了肝细胞的铁死亡和 THP-1 细胞对 RBC 的吞噬作用。激活的血小板在 NASH 中增强的肝红细胞吞噬作用加剧了 HIO。西洛他唑可防止异位红细胞吞噬作用，从而减轻 NASH 模型中 HIO 介导的铁死亡。
