title: Dyslipidemic diabetic serum increases lipid accumulation and expression of stearoyl-CoA desaturase in human macrophages.
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.
authors.affiliation: School of Medicine and Pharmacology, Fremantle and Royal Perth Hospitals, University of Western Australia, Perth, WA, Australia.
authors.forename: Bruce X W
authors.initials: BX
authors.lastname: Wong
authors.forename: Reece A
authors.initials: RA
authors.lastname: Kyle
authors.forename: Paul C
authors.initials: PC
authors.lastname: Myhill
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Croft
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Quinn
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
authors.forename: Bu B
authors.initials: BB
authors.lastname: Yeap
mesh_terms: D000328:Adult; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications; D050171:Dyslipidemias / Q000097:blood* / Q000150:complications; D005227:Fatty Acids / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008264:Macrophages / Q000201:enzymology*; D034741:RNA, Small Interfering / Q000235:genetics; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; D034741:RNA, Small Interfering; D051117:Scavenger Receptors, Class A; D013230:Stearoyl-CoA Desaturase