Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain; Department of Medicine, Universitat de Girona, Girona, Spain.
Biomed Pharmacother. 2023 Oct;166:115428. doi: 10.1016/j.biopha.2023.115428. Epub 2023 Sep 6.
The association among increased inflammation, disrupted iron homeostasis, and adipose tissue dysfunction in obesity has been widely recognized. However, the specific impact of inflammation on iron homeostasis during human adipogenesis and in adipocytes remains poorly understood. In this study, we investigated the effects of bacterial lipopolysaccharide (LPS) on iron homeostasis during human adipocyte differentiation, in fully differentiated adipocytes, and in human adipose tissue. We found that LPS-induced inflammation hindered adipogenesis and led to a gene expression profile indicative of intracellular iron accumulation. This was accompanied by increased expression of iron importers (TFRC and SLC11A2), markers of intracellular iron accumulation (FTH, CYBA, FTL, and LCN2), and decreased expression of iron exporter-related genes (SLC40A1), concomitant with elevated intracellular iron levels. Mechanistically, RNA-seq analysis and gene knockdown experiments revealed the significant involvement of iron importers SLC39A14, SLC39A8, and STEAP4 in LPS-induced intracellular iron accumulation in human adipocytes. Notably, markers of LPS signaling pathway-related inflammation were also associated with a gene expression pattern indicative of intracellular iron accumulation in human adipose tissue, corroborating the link between LPS-induced inflammation and iron accumulation at the tissue level. In conclusion, our findings demonstrate that induction of adipocyte inflammation disrupts iron homeostasis, resulting in adipocyte iron overload.
人们广泛认识到，肥胖症中炎症增加、铁稳态紊乱和脂肪组织功能障碍之间存在关联。然而，炎症对人类脂肪生成过程中和脂肪细胞中的铁稳态的具体影响仍知之甚少。在这项研究中，我们研究了细菌脂多糖（LPS）在人类脂肪细胞分化过程中、在完全分化的脂肪细胞中和在人体脂肪组织中对铁稳态的影响。我们发现，LPS 诱导的炎症会阻碍脂肪生成，并导致细胞内铁积累的基因表达谱。这伴随着铁摄取体（TFRC 和 SLC11A2）、细胞内铁积累标志物（FTH、CYBA、FTL 和 LCN2）的表达增加，以及铁输出相关基因（SLC40A1）的表达减少，同时细胞内铁水平升高。从机制上讲，RNA-seq 分析和基因敲低实验表明，铁摄取体 SLC39A14、SLC39A8 和 STEAP4 在 LPS 诱导的人类脂肪细胞内铁积累中起着重要作用。值得注意的是，LPS 信号通路相关炎症标志物也与人体脂肪组织中细胞内铁积累的基因表达模式相关，这证实了 LPS 诱导的炎症与组织水平的铁积累之间的联系。总之，我们的研究结果表明，脂肪细胞炎症的诱导会破坏铁稳态，导致脂肪细胞铁过载。
