Faculty Collaboration Database

MEK1/2 inhibitors activate macrophage ABCG1 expression and reverse cholesterol transport-An anti-atherogenic function of ERK1/2 inhibition. Biochim Biophys Acta 2016 Sep;1861(9 Pt A):1180-1191

Date

07/02/2016

Pubmed ID

27365310

DOI

10.1016/j.bbalip.2016.06.017

Scopus ID

2-s2.0-84978045117 (requires institutional sign-in at Scopus site)   20 Citations

Abstract

Expression of ATP-binding cassette transporter G1 (ABCG1), a molecule facilitating cholesterol efflux to HDL, is activated by liver X receptor (LXR). In this study, we investigated if inhibition of ERK1/2 can activate macrophage ABCG1 expression and functions. MEK1/2 inhibitors, PD98059 and U0126, increased ABCG1 mRNA and protein expression, and activated the natural ABCG1 promoter but not the promoter with the LXR responsive element (LXRE) deletion. Inhibition of ABCG1 expression by ABCG1 siRNA did enhance the formation of macrophage/foam cells and it attenuated the inhibitory effect of MEK1/2 inhibitors on foam cell formation. MEK1/2 inhibitors activated macrophage cholesterol efflux to HDL in vitro, and they enhanced reverse cholesterol transport (RCT) in vivo. ApoE deficient (apoE(-/-)) mice receiving U0126 treatment had reduced sinus lesions in the aortic root which was associated with activated macrophage ABCG1 expression in the lesion areas. MEK1/2 inhibitors coordinated the RXR agonist, but not the LXR agonist, to induce ABCG1 expression. Furthermore, induction of ABCG1 expression by MEK1/2 inhibitors was associated with activation of SIRT1, a positive regulator of LXR activity, and inactivation of SULT2B1 and RIP140, two negative regulators of LXR activity. Taken together, our study suggests that MEK1/2 inhibitors activate macrophage ABCG1 expression/RCT, and inhibit foam cell formation and lesion development by multiple mechanisms, supporting the concept that ERK1/2 inhibition is anti-atherogenic.

Author List

Zhang L, Chen Y, Yang X, Yang J, Cao X, Li X, Li L, Miao QR, Hajjar DP, Duan Y, Han J

MESH terms used to index this publication - Major topics in bold

Animals
Aorta
Apolipoproteins E
Atherosclerosis
Biological Transport
Butadienes
Cholesterol
Flavonoids
Foam Cells
Gene Expression Regulation
Humans
Liver X Receptors
MAP Kinase Kinase 1
MAP Kinase Signaling System
Macrophages
Mice
Mice, Knockout
Nitriles
Promoter Regions, Genetic
Retinoid X Receptor alpha
Sirtuin 1