Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1865, Issue 2, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbalip.2019.158531
Keywords
Atherosclerosis; Hepcidin; Iron; Macrophages; Cholesterol
Funding
- National Natural Science Foundation of China [81472979, 81172658, 81402673, 81703226]
Ask authors/readers for more resources
Iron accumulation has been frequently found in atherosclerotic lesions, especially in macrophages/foam cells, but the exact mechanisms by which hepcidin induces iron retention in plaque macrophages and its roles in atherogenesis remain unknown. Double immunofluorescence staining showed colocalization of hepcidin-positive macrophages with ox-LDL, TLR4, p-p65 and ferritin light chain (ferritin-L) both in human and murine atherosclerotic lesions. RAW264.7 macrophages incubated with ox-LDL showed elevated expression of TLR4, p-p65, hepcidin, ferritin-L/H, CYP27A1, CD36, PPAR gamma, liver X receptor alpha (LXR alpha), and ATP binding cassette transporter A1/G1 (ABCA1/G1), as well as increased intracellular labile iron pool level and lipid accumulation. Ox-LDL-induced iron retention and lipid accumulation were aggravated by lipopolysaccharide but blocked by TAK-242, an antagonist of TLR4. Moreover, macrophage TLR4/NF-kappa B pathway activation and foaming triggered by ox-LDL was enhanced by ferric ammonium citrate or exogenous hepcidin but attenuated by hepcidin silencing or the use of iron chelator. Meanwhile, the addition of hepcidin stimulated CD36-mediated Dil-labeled-ox-LDL uptake and inhibited the LXR alpha-ABCA1/G1 pathway-dependent cholesterol efflux in macrophages, which was significantly reversed by 27-hydroxycholesterol but further exacerbated by cyclosporin A, a selective inhibitor of CYP27A1. Our study provided the evidence that iron trapped in atherosclerosis plaque macrophages contributes to cholesterol disequilibrium-initiated foam cell formation, which is provoked by the unique but largely unknown autocrine formation of hepcidin in plaque macrophages via activating the TLR4/NF-kappa B pathway when exposed to ox-LDL. Such findings, considering the intricate vicious cycle between macrophage hepcidin autocrine-triggered iron retention and cholesterol disequilibrium, may shed new light on the iron hypothesis of atherosclerosis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available