TY - JOUR
T1 - LIM-only protein FHL2 is a positive regulator of liver X receptors in smooth muscle cells involved in lipid homeostasis
AU - Kurakula, Kondababu
AU - Sommer, Daniela
AU - Sokolovic, Milka
AU - Moerland, Perry D.
AU - Scheij, Saskia
AU - van Loenen, Pieter B.
AU - Koenis, Duco S.
AU - Zelcer, Noam
AU - van Tiel, Claudia M.
AU - de Vries, Carlie J.M.
N1 - Publisher Copyright: © 2015, American Society for Microbiology.
PY - 2015
Y1 - 2015
N2 - The LIM-only protein FHL2 is expressed in smooth muscle cells (SMCs) and inhibits SMC-rich-lesion formation. To further elucidate the role of FHL2 in SMCs, we compared the transcriptomes of SMCs derived from wild-type (WT) and FHL2 knockout (KO) mice. This revealed that in addition to the previously recognized involvement of FHL2 in SMC proliferation, the cholesterol synthesis and liver X receptor (LXR) pathways are altered in the absence of FHL2. Using coimmunoprecipitation experiments, we found that FHL2 interacts with the two LXR isoforms, LXRα and LXRβ. Furthermore, FHL2 strongly enhances transcriptional activity of LXR element (LXRE)-containing reporter constructs. Chromatin immunoprecipitation (ChIP) experiments on the ABCG1 promoter revealed that FHL2 enhances the association of LXRβ with DNA. In line with these observations, we observed reduced basal transcriptional LXR activity in FHL2-KO SMCs compared to WT SMCs. This was also reflected in reduced expression of LXR target genes in intact aorta and aortic SMCs of FHL2-KO mice. Functionally, the absence of FHL2 resulted in attenuated cholesterol efflux to both ApoA-1 and high-density lipoprotein (HDL), in agreement with reduced LXR signaling. Collectively, our findings demonstrate that FHL2 is a transcriptional coactivator of LXRs and points toward FHL2 being an important determinant of cholesterol metabolism in SMCs.
AB - The LIM-only protein FHL2 is expressed in smooth muscle cells (SMCs) and inhibits SMC-rich-lesion formation. To further elucidate the role of FHL2 in SMCs, we compared the transcriptomes of SMCs derived from wild-type (WT) and FHL2 knockout (KO) mice. This revealed that in addition to the previously recognized involvement of FHL2 in SMC proliferation, the cholesterol synthesis and liver X receptor (LXR) pathways are altered in the absence of FHL2. Using coimmunoprecipitation experiments, we found that FHL2 interacts with the two LXR isoforms, LXRα and LXRβ. Furthermore, FHL2 strongly enhances transcriptional activity of LXR element (LXRE)-containing reporter constructs. Chromatin immunoprecipitation (ChIP) experiments on the ABCG1 promoter revealed that FHL2 enhances the association of LXRβ with DNA. In line with these observations, we observed reduced basal transcriptional LXR activity in FHL2-KO SMCs compared to WT SMCs. This was also reflected in reduced expression of LXR target genes in intact aorta and aortic SMCs of FHL2-KO mice. Functionally, the absence of FHL2 resulted in attenuated cholesterol efflux to both ApoA-1 and high-density lipoprotein (HDL), in agreement with reduced LXR signaling. Collectively, our findings demonstrate that FHL2 is a transcriptional coactivator of LXRs and points toward FHL2 being an important determinant of cholesterol metabolism in SMCs.
UR - http://www.scopus.com/inward/record.url?scp=84920059285&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/MCB.00525-14
DO - https://doi.org/10.1128/MCB.00525-14
M3 - Article
C2 - 25332231
SN - 0270-7306
VL - 35
SP - 52
EP - 62
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 1
ER -