Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathwaysResearch in context
Background: 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 investigate...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-03-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419300714 |
| _version_ | 1828937936053207040 |
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| author | Xiaoquan Rao Shi Zhao Zachary Braunstein Hong Mao Michael Razavi Lihua Duan Yingying Wei Amelia C. Toomey Sanjay Rajagopalan Jixin Zhong |
| author_facet | Xiaoquan Rao Shi Zhao Zachary Braunstein Hong Mao Michael Razavi Lihua Duan Yingying Wei Amelia C. Toomey Sanjay Rajagopalan Jixin Zhong |
| author_sort | Xiaoquan Rao |
| collection | DOAJ |
| description | Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Keywords: Dipeptidyl peptidase IV, Inflammation, Obesity, Atherosclerosis, Oxidized LDL |
| first_indexed | 2024-12-14T02:34:27Z |
| format | Article |
| id | doaj.art-c1fad7d7cd644a7b989b6d30c2b0fb6c |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-14T02:34:27Z |
| publishDate | 2019-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-c1fad7d7cd644a7b989b6d30c2b0fb6c2022-12-21T23:20:10ZengElsevierEBioMedicine2352-39642019-03-01415061Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathwaysResearch in contextXiaoquan Rao0Shi Zhao1Zachary Braunstein2Hong Mao3Michael Razavi4Lihua Duan5Yingying Wei6Amelia C. Toomey7Sanjay Rajagopalan8Jixin Zhong9Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA; Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USADepartment of Endocrinology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Correspondence to: S. Zhao, Department of Endocrinology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China.Department of Internal Medicine, Wexnel Medical Center, The Ohio State University, Columbus, OH, USADepartment of Endocrinology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaCardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USACardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USACardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USADepartment of Health Sciences, University of Missouri, Columbia, MO, USACardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USACardiovascular Research Institute, Case Western Reserve University, Cleveland, OH, USA; Correspondence to: J. Zhong, 2103 Cornell Road. Wolstein Research Build RM 4525, Cleveland, OH 44106, USA.Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Keywords: Dipeptidyl peptidase IV, Inflammation, Obesity, Atherosclerosis, Oxidized LDLhttp://www.sciencedirect.com/science/article/pii/S2352396419300714 |
| spellingShingle | Xiaoquan Rao Shi Zhao Zachary Braunstein Hong Mao Michael Razavi Lihua Duan Yingying Wei Amelia C. Toomey Sanjay Rajagopalan Jixin Zhong Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathwaysResearch in context EBioMedicine |
| title | Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathwaysResearch in context |
| title_full | Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathwaysResearch in context |
| title_fullStr | Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathwaysResearch in context |
| title_full_unstemmed | Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathwaysResearch in context |
| title_short | Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathwaysResearch in context |
| title_sort | oxidized ldl upregulates macrophage dpp4 expression via tlr4 trif cd36 pathwaysresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419300714 |
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