RT Journal Article
SR Electronic
T1 Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 615872
DO 10.1101/615872
A1 Jessica M Johnston
A1 Adrienn Angyal
A1 Robert C Bauer
A1 Stephen Hamby
A1 S Kim Suvarna
A1 Kajus Baidžajevas
A1 Zoltan Hegedus
A1 T Neil Dear
A1 Martin Turner
A1 The Cardiogenics Consortium
A1 Heather L Wilson
A1 Alison H Goodall
A1 Daniel J Rader
A1 Carol C Shoulders
A1 Sheila E Francis
A1 Endre Kiss-Toth
YR 2019
UL http://biorxiv.org/content/early/2019/05/05/615872.abstract
AB Macrophages drive atherosclerotic plaque progression and rupture, hence attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.