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Dyslipidemic Diabetic Serum Increases Lipid Accumulation and Expression of Stearoyl-CoA Desaturase in Human Macrophages

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Lipids

Abstract

Type 2 diabetes and dyslipidemia are risk factors for cardiovascular disease. However, mechanisms by which hypertriglyceridemia influences atherogenesis remain unclear. We examined effects of dyslipidemic diabetic serum on macrophage lipid accumulation as a model of foam cell formation. Normal human macrophages were cultured in media supplemented with 10% serum from non-diabetic normolipidemic or non-diabetic hypercholesterolemic adults versus adults with Type 2 diabetes; diabetes and hypertriglyceridemia; or diabetes and hypercholesterolemia. Exposure to diabetic sera resulted in increased macrophage fatty acids (2–3 fold higher, both saturated and unsaturated). Macrophage expression of CD36, scavenger receptor A (SR-A) and stearoyl-CoA desaturase (SCD) was increased, most prominently in macrophages exposed to hypertriglyceridemic diabetic serum (twofold increase in CD36 and fourfold increase in SCD, p < 0.05). In these conditions, RNA inhibition of CD36 reduced macrophage free cholesterol (163.9 ± 10.5 vs. 221.9 ± 26.2 mmol free cholesterol/g protein, p = 0.04). RNA inhibition of SCD decreased macrophage fatty acid content, increased ABCA1 level and enhanced cholesterol efflux (18.0 ± 3.9 vs. 8.0 ± 0.8% at 48 h, p = 0.03). Diabetic dyslipidemia may contribute to accelerated atherosclerosis via alterations in macrophage lipid metabolism favoring foam cell formation. Increased expression of CD36 and SR-A would facilitate macrophage lipid uptake, while increased expression of SCD could block compensatory upregulation of ABCA1 and cholesterol efflux. Further studies are needed to clarify whether modulation of macrophage lipid metabolism might reduce progression of diabetic atherosclerosis.

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Abbreviations

ABCA1:

ATP-binding cassette transporter A1

ABCG1:

ATP-binding cassette transporter G1

CD36:

Cluster of differentiation 36

CE:

Cholesterol ester

CVD:

Cardiovascular disease

FA:

Fatty acid(s)

FC:

Free cholesterol

GC:

Gas chromatography

GC–MS:

Gas chromatography–mass spectrometry

HDL:

High density lipoprotein

hMDM:

Human monocyte-derived macrophage(s)

LDL:

Low density lipoprotein

LXR:

Liver X receptor

PPARγ:

Peroxisome proliferator-activated receptor gamma

RNAi:

RNA inhibition

SCD:

Stearoyl-CoA desaturase

siRNA:

Small interfering RNA

SR-A:

Scavenger receptor A

TG:

Triglyceride

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Acknowledgments

We thank staff from Biochemistry, Specimen Reception and Transfusion Medicine, Fremantle Hospital for their assistance with this project, and the Australian Red Cross Blood Service for providing buffy coats. This work was supported by research Grants from the National Heart Foundation of Australia (G07 P3159), the Raine Medical Foundation of Western Australia, the University of Western Australia and the Fremantle Hospital Medical Research Foundation, Western Australia.

Conflict of interest

The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. School of Medicine and Pharmacology, Fremantle and Royal Perth Hospitals, University of Western Australia, Perth, WA, Australia

    Bruce X. W. Wong, Reece A. Kyle, Kevin D. Croft & Bu B. Yeap

  2. Department of Endocrinology and Diabetes, Fremantle Hospital, Fremantle, WA, Australia

    Paul C. Myhill & Bu B. Yeap

  3. Centre for Vascular Research, University of New South Wales, Sydney, NSW, Australia

    Carmel M. Quinn & Wendy Jessup

  4. School of Medicine and Pharmacology, Level 2, T-Block, Fremantle Hospital, Alma Street, Fremantle, WA, 6160, Australia

    Bu B. Yeap

Authors
  1. Bruce X. W. Wong
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Correspondence to Bu B. Yeap.

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Wong, B.X.W., Kyle, R.A., Myhill, P.C. et al. Dyslipidemic Diabetic Serum Increases Lipid Accumulation and Expression of Stearoyl-CoA Desaturase in Human Macrophages. Lipids 46, 931–941 (2011). https://doi.org/10.1007/s11745-011-3578-5

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  • DOI: https://doi.org/10.1007/s11745-011-3578-5

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