Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathways

Xiaoquan Rao, Shi Zhao, Zachary Braunstein, Hong Mao, Michael Razavi, Lihua Duan, Yingying Wei, Amelia C. Toomey, Sanjay Rajagopalan, Jixin Zhong

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalEBioMedicine
DOIs
StatePublished - Jan 1 2019

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Toll-Like Receptor 4
Macrophages
Up-Regulation
Monocytes
Atherosclerosis
Body Mass Index
Obesity
Dipeptidyl Peptidase 4
Immunophenotyping
Flow cytometry
Metabolism
Lipoproteins
Meals
Blood Glucose
Assays
Flow Cytometry
Triglycerides
Peptide Hydrolases
Cholesterol
oxidized low density lipoprotein

Keywords

  • Atherosclerosis
  • Dipeptidyl peptidase IV
  • Inflammation
  • Obesity
  • Oxidized LDL

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathways. / Rao, Xiaoquan; Zhao, Shi; Braunstein, Zachary; Mao, Hong; Razavi, Michael; Duan, Lihua; Wei, Yingying; Toomey, Amelia C.; Rajagopalan, Sanjay; Zhong, Jixin.

In: EBioMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Rao, X, Zhao, S, Braunstein, Z, Mao, H, Razavi, M, Duan, L, Wei, Y, Toomey, AC, Rajagopalan, S & Zhong, J 2019, 'Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathways', EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.01.065
Rao, Xiaoquan ; Zhao, Shi ; Braunstein, Zachary ; Mao, Hong ; Razavi, Michael ; Duan, Lihua ; Wei, Yingying ; Toomey, Amelia C. ; Rajagopalan, Sanjay ; Zhong, Jixin. / Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathways. In: EBioMedicine. 2019.
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keywords = "Atherosclerosis, Dipeptidyl peptidase IV, Inflammation, Obesity, Oxidized LDL",
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AU - Rao, Xiaoquan

AU - Zhao, Shi

AU - Braunstein, Zachary

AU - Mao, Hong

AU - Razavi, Michael

AU - Duan, Lihua

AU - Wei, Yingying

AU - Toomey, Amelia C.

AU - Rajagopalan, Sanjay

AU - Zhong, Jixin

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Dipeptidyl peptidase IV

KW - Inflammation

KW - Obesity

KW - Oxidized LDL

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