Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA; Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA.
Department of Endocrinology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
EBioMedicine. 2019 Mar;41:50-61. doi: 10.1016/j.ebiom.2019.01.065. Epub 2019 Feb 7.
We and others have shown that dipeptidyl peptidase-IV (DPP4) expression is increased in obesity/atherosclerosis and is positively correlated with atherosclerotic burden. However, the mechanism by which DPP4 expression is regulated in obesity remains unclear. In this study, we investigated the pathways regulating the expression of DPP4 on macrophages.
Flowsight® Imaging Flow Cytometry was employed for the detection of DPP4 and immunophenotyping. DPP4 enzymatic activity was measured by a DPPIV-Glo™ Protease Assay kit.
Human monocytes expressed a moderate level of membrane-bound DPP4. Obese patients with body mass index (BMI) ≥ 30 had a higher level of monocyte DPP4 expression, in parallel with higher levels of HOMA-IR, blood glucose, triglycerides, and non-HDL cholesterol, compared to those in the non-obese (BMI < 30) patients. Oxidized low-density lipoprotein (oxLDL), but not native LDL, up-regulated DPP4 expression on macrophages with a preferential increase in CD36 cells. OxLDL mediated DPP4 up-regulation was considerably diminished by Toll-like receptor-4 (TLR4) knockdown and CD36 deficiency. TRIF deficiency, but not MyD88 deficiency, attenuated oxLDL-induced DPP4 increase.
Our study suggests a key role for oxLDL and downstream CD36/TLR4/TRIF in regulating DPP4 expression. Increased DPP4 in response to oxidized lipids may represent an integrated mechanism linking post-prandial glucose metabolism to lipoprotein abnormality-potentiated atherosclerosis.
我们和其他人已经表明，二肽基肽酶-IV（DPP4）的表达在肥胖/动脉粥样硬化中增加，并且与动脉粥样硬化负担呈正相关。然而，DPP4 表达在肥胖中受何种机制调节仍不清楚。在这项研究中，我们研究了调节巨噬细胞中 DPP4 表达的途径。
采用 Flowsight®成像流式细胞术检测 DPP4 和免疫表型。通过 DPPIV-Glo™蛋白酶测定试剂盒测量 DPP4 酶活性。
人单核细胞表达中等水平的膜结合 DPP4。肥胖患者的 BMI（体重指数）≥30 时，单核细胞 DPP4 表达水平更高，与非肥胖患者（BMI＜30）相比，其 HOMA-IR、血糖、甘油三酯和非高密度脂蛋白胆固醇水平也更高。与天然 LDL 相比，氧化型 LDL（oxLDL）而非天然 LDL 上调了巨噬细胞上的 DPP4 表达，且 CD36 细胞的表达增加更为明显。Toll 样受体 4（TLR4）敲低和 CD36 缺乏可显著减少 oxLDL 介导的 DPP4 上调。TRIF 缺陷而非 MyD88 缺陷可减轻 oxLDL 诱导的 DPP4 增加。
我们的研究表明 oxLDL 和下游 CD36/TLR4/TRIF 在调节 DPP4 表达中起关键作用。对氧化脂质的反应增加的 DPP4 可能代表一种综合机制，将餐后葡萄糖代谢与脂蛋白异常增强的动脉粥样硬化联系起来。
