Although previous studies have shown that the administration of fibroblast growth factor 21 (FGF21) reverses hepatic steatosis, the mechanism by which FGF21 exerts a therapeutic effect on nonalcoholic fatty liver disease (NAFLD) is not yet entirely understood. We previously demonstrated that hepatic six transmembrane protein of prostate 2 (STAMP2) may represent a suitable target for NAFLD. We investigated the mechanism underlying the therapeutic effect of recombinant FGF21 on NAFLD, focusing on the involvement of hepatic STAMP2. In this study, we used human nonalcoholic steatosis patient pathology samples, C57BL/6 mice for a high‐fat diet (HFD)‐induced in vivo NAFLD model, and used human primary hepatocytes and HepG2 cells for oleic acid (OA)‐induced in vitro NAFLD model. We observed that recombinant FGF21 treatment ameliorated hepatic steatosis and insulin resistance through the upregulation of STAMP2 expression. We further observed hepatic iron overload (HIO) and reduced iron exporter, ferroportin expression in the liver samples obtained from human NAFLD patients, and HFD‐induced NAFLD mice and in OA‐treated HepG2 cells. Importantly, recombinant FGF21 improved HIO through the hepatic STAMP2‐mediated upregulation of ferroportin expression. Our data suggest that hepatic STAMP2 may represent a suitable therapeutic intervention target for FGF21‐induced improvement of NAFLD accompanying HIO.

中文翻译：

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肝 STAMP2 介导重组 FGF21 诱导的非酒精性脂肪性肝病肝铁过载改善

尽管之前的研究表明，给予成纤维细胞生长因子 21 (FGF21) 可以逆转肝脏脂肪变性，但 FGF21 对非酒精性脂肪肝 (NAFLD) 发挥治疗作用的机制尚不完全清楚。我们之前已经证明，前列腺 2 的肝六跨膜蛋白（STAMP2）可能是 NAFLD 的合适靶点。我们研究了重组 FGF21 对 NAFLD 治疗作用的潜在机制，重点是肝脏 STAMP2 的参与。在这项研究中，我们使用人类非酒精性脂肪变性患者病理样本、C57BL/6 小鼠进行高脂肪饮食 (HFD) 诱导的体内 NAFLD 模型，并使用人类原代肝细胞和 HepG2 细胞进行油酸 (OA) 诱导的体内 NAFLD 模型。体外 NAFLD 模型。我们观察到重组 FGF21 治疗通过上调 STAMP2 表达来改善肝脏脂肪变性和胰岛素抵抗。我们进一步观察到肝脏铁过载 (HIO) 和铁输出蛋白减少、从人类 NAFLD 患者、HFD 诱导的 NAFLD 小鼠和 OA 处理的 HepG2 细胞获得的肝脏样本中铁转运蛋白的表达。重要的是，重组 FGF21 通过肝 STAMP2 介导的铁转运蛋白表达上调改善了 HIO。我们的数据表明，肝脏 STAMP2 可能代表 FGF21 诱导的 NAFLD 改善伴随 HIO 的合适治疗干预目标。和 HFD 诱导的 NAFLD 小鼠和 OA 处理的 HepG2 细胞。重要的是，重组 FGF21 通过肝 STAMP2 介导的铁转运蛋白表达上调改善了 HIO。我们的数据表明，肝脏 STAMP2 可能代表 FGF21 诱导的 NAFLD 改善伴随 HIO 的合适治疗干预目标。和 HFD 诱导的 NAFLD 小鼠和 OA 处理的 HepG2 细胞。重要的是，重组 FGF21 通过肝 STAMP2 介导的铁转运蛋白表达上调改善了 HIO。我们的数据表明，肝脏 STAMP2 可能代表 FGF21 诱导的 NAFLD 改善伴随 HIO 的合适治疗干预目标。