Shayo Sigfrid Casmir, Ogiso Kazuma, Kawade Shigeru, Hashiguchi Hiroshi, Deguchi Takahisa, Nishio Yoshihiko
Department of Diabetes and Endocrine Medicine, Kagoshima University Graduate School of Medical and Dental Science, 8‑35‑1 Sakuragaoka, Kagoshima, 890‑8520 Japan.
Muhimbili University of Health and Allied Sciences, P.O.BOX 65001, Dar es Salaam, Tanzania.
Diabetol Int. 2021 Sep 26;13(2):358-371. doi: 10.1007/s13340-021-00542-1. eCollection 2022 Apr.
The balance between pro-atherogenic and anti-atherogenic factors is very crucial in the development of atherosclerotic lesions. Although the expression of the six-transmembrane epithelial antigen of the prostate 4 (STEAP4) in myeloid cells is known to be atheroprotective, there is not a single study reporting on the status of STEAP4 expression in circulating monocytes in the early stages of diet-induced obesity or in events of glycemic excursions.
We induced glycemic spikes twice daily for a 1-week duration to rats fed on regular chow and western diet, and analyzed gene expression changes in the peripheral blood mononuclear cells (PBMCs). We also conducted experiments on RAW 264.7 cells to gain insight into some of our in vivo findings.
Diet-induced obesity and glycemic excursions independently caused a significant increase in STEAP4 mRNA expression in PBMCs. This was also accompanied by an induction of a substantial number of pro-inflammatory cytokines, chemokines, and chemokine receptors. However, the combined effect of western diet and hyperglycemic spikes was subtle and non-additive. In the in vitro setting, either glucose spikes, persistent hyperglycemia, or a combination of palmitic acid and insulin resulted in a parallel increase in expression of STEAP4 and pro-inflammatory genes. This was, however, significantly abrogated with 4-octyl itaconate or attenuated by inhibitors of p38MAPK and NF-kB.
STEAP4 expression in mononuclear cells is induced by increasing inflammation or oxidative stress. The observed increase in STEAP4 expression in circulating monocytes due to visceral obesity or glycemic excursions is a compensatory response.
The online version contains supplementary material available at 10.1007/s13340-021-00542-1.
促动脉粥样硬化因子和抗动脉粥样硬化因子之间的平衡在动脉粥样硬化病变的发展过程中至关重要。虽然已知前列腺六次跨膜上皮抗原4（STEAP4）在髓样细胞中的表达具有抗动脉粥样硬化作用，但尚无研究报道饮食诱导肥胖早期或血糖波动情况下循环单核细胞中STEAP4的表达状况。
我们对喂食普通饲料和西式饮食的大鼠每天诱导两次血糖峰值，持续1周，并分析外周血单个核细胞（PBMCs）中的基因表达变化。我们还对RAW 264.7细胞进行了实验，以深入了解我们的一些体内研究结果。
饮食诱导的肥胖和血糖波动分别导致PBMCs中STEAP4 mRNA表达显著增加。这还伴随着大量促炎细胞因子、趋化因子和趋化因子受体的诱导。然而，西式饮食和高血糖峰值的联合作用较为微妙，且无叠加效应。在体外环境中，无论是葡萄糖峰值、持续性高血糖，还是棕榈酸与胰岛素的组合，都会导致STEAP4和促炎基因的表达同时增加。然而，这一现象可被4-辛基衣康酸显著消除，或被p38丝裂原活化蛋白激酶（p38MAPK）和核因子κB（NF-κB）抑制剂减弱。
单核细胞中STEAP4的表达是由炎症或氧化应激增加所诱导的。内脏肥胖或血糖波动导致循环单核细胞中STEAP4表达增加是一种代偿反应。
在线版本包含可在10.1007/s13340-021-00542-1获取的补充材料。
