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Small HDL, diabetes, and proinflammatory effects in macrophages
Author(s) -
Kothari Vishal,
He Yi,
Kramer Farah,
Barnhart Shelley,
Kanter Jenny E,
Tang Jingjing,
Frey Jeremy M,
Vaisar Tomas,
Heinecke Jay W,
Bornfeldt Karin E
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.238.3
Subject(s) - proinflammatory cytokine , endocrinology , medicine , cholesterol , abca1 , ldl receptor , apolipoprotein b , reverse cholesterol transport , population , high density lipoprotein , lipoprotein , inflammation , diabetes mellitus , chemistry , biochemistry , transporter , environmental health , gene
Atherosclerosis, an inflammatory disease of the arterial wall, is the commonest cause of cardiovascular disease (CVD) events. Elevated levels of high‐density lipoprotein (HDL) cholesterol are generally believed to protect against CVD and to reduce inflammatory activation of macrophages, a key cell type in lesions of atherosclerosis. However, HDL can also exert proinflammatory effects in macrophages by inducing cholesterol depletion. Because small HDL (7–8.5 nm diameter) is most effective in removing cholesterol from cells by the ABCA1 pathway, we hypothesized that small HDL is the most proinflammatory HDL population. Small‐, medium‐ and large HDL populations were isolated from a human apolipoprotein A‐I transgenic LDL receptor‐deficient mouse model ( APOA1 Tg ;Ldlr − / − ). Depletion of cholesterol by HDL increased the ability of toll‐like receptor (TLR) ligands to induce proinflammatory mediators in macrophages. This effect was prevented by cholesterol loading of the macrophages. Small HDL had a significantly stronger effect on Tnfa (3‐fold over LPS alone) and Il1b (2.5‐fold over LPS alone) gene expression than medium or large HDL particles. Inhibition or deletion of the sheddase ADAM17 in macrophages prevented the proinflammatory effects of HDL. Patients with type 1 diabetes mellitus (T1DM) exhibit an increased risk of CVD despite having normal or high HDL‐cholesterol. To investigate the effect of diabetes on HDL subpopulations, we crossed a virally‐induced mouse model of T1DM ( Ldlr − / − ;Gp Tg ) with the human APOA1 Tg ;Ldlr − / − mouse. The mice ( APOA1 Tg ;Ldlr − / − ;Gp Tg , n=8–10) were injected with a liver‐specific adeno‐associated virus driving expression of human cholesteryl ester transfer protein (hCETP) to mimic human physiology. Diabetic mice had an increased HDL particle concentration (~2‐fold) associated with a significant increase in serum HDL cholesterol efflux capacity through both ABCA1 and ABCG1, compared with non‐diabetic mice. The largest increase was in the small HDL particle concentration (15 μM vs 6 μM in non‐diabetic mice). Moreover, resident peritoneal macrophages from diabetic mice exhibited increased cytokine gene expression, as compared with non‐diabetic littermates. Our findings demonstrate that higher levels of small HDL, as observed in a mouse model of diabetes, can exacerbate inflammatory activation in non‐lipid loaded macrophages in an ADAM17‐dependent manner. We have found similar changes in HDL concentration and function in humans with T1DM, suggesting that our mouse model might provide novel insights into CVD risk in T1DM patients. Support or Funding Information funded in part by the National Institutes of Health, grants DP3DK108209, P01HL092969, P30 DK017047, and P01HL128203 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .