Resistin increases lipid accumulation by affecting class A scavenger receptor, CD36 and ATP-binding cassette transporter-A1 in macrophages.
OBJECTIVE
Resistin promotes macrophage-foam cell formation, but the mechanisms are unclear. In macrophages, lipid uptake is regulated by scavenger receptors (SR-A and CD36), while the cholesterol efflux is regulated by SR-BI, ATP-binding cassette transporter-A1 (ABCA1) and ABCG1. We investigated the mechanisms underlying the dysregulation by resistin of these regulators leading to promotion of lipid accumulation in bone marrow-derived macrophages.


METHODS
Western blotting, real-time PCR and oil red O staining were performed.


RESULTS
Resistin exacerbated lipid accumulation in oxLDL-treated macrophages. Resistin treatment of oxLDL-untreated macrophages showed increased SR-A and CD36 mRNA and protein levels, and decreased ABCA1 protein level, while having no effect on SR-BI or ABCG1 expression. Up-regulation of SR-A and CD36 by resistin resulted from activation of AP-1 and PPARgamma, respectively, and this was confirmed by the lack of activation of either after AP-1 inhibition using curcumin or SP600125, or PPARgamma inhibition using GW9662, respectively. The down-regulation of ABCA1 by resistin was not accompanied by a reduced mRNA level or an activation of LXRalpha/RXR, but resulted from enhanced protein degradation as revealed by the abolition of the down-regulation after inhibition of the proteasome pathway using ALLN or MG-132. A combined inhibition by SP600125, GW9662 and ALLN prevented resistin-induced exacerbation of lipid accumulation in oxLDL-treated macrophages.


CONCLUSIONS
Resistin promotes foam cell formation via dysregulation of SR-A, CD36 and ABCA1. SR-A and CD36 are transcriptionally up-regulated by resistin through AP-1 and PPARgamma, respectively, whereas ABCA1 is down-regulated by resistin through proteasome-mediated enhancement of protein degradation.
Lee
Tzong-Shyuan
TS
Institute of Physiology, School of Medicine, National Yang-Ming University, Taiwan.
Lin
Chun-Yueh
CY
Tsai
Jin-Yi
JY
Wu
Yuh-Lin
YL
Su
Kuo-Hui
KH
Lu
Kuo-Yun
KY
Hsiao
Sheng-Huang
SH
Pan
Ching-Chian
CC
Kou
Yu Ru
YR
Hsu
Yung-Pei
YP
Ho
Low-Tone
LT
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D018955:CD36 Antigens / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D047495:PPAR gamma / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D052243:Resistin / Q000502:physiology*; D051117:Scavenger Receptors, Class A / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; C008132:Cd36 protein, rat; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D052243:Resistin; C499622:Retn protein, rat; D051117:Scavenger Receptors, Class A; D018808:Transcription Factor AP-1; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D046988:Proteasome Endopeptidase Complex