title: LIM-only protein FHL2 is a positive regulator of liver X receptors in smooth muscle cells involved in lipid homeostasis.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Kondababu
authors.initials: K
authors.lastname: Kurakula
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sommer
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands European Food Information Council, Brussels, Belgium.
authors.forename: Milka
authors.initials: M
authors.lastname: Sokolovic
authors.affiliation: Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Scheij
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Pieter B
authors.initials: PB
authors.lastname: van Loenen
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Duco S
authors.initials: DS
authors.lastname: Koenis
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: van Tiel
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands c.j.devries@amc.nl.
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D006367:HeLa Cells; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C105987:FHL2 protein, human; C491382:Fhl2 protein, mouse; D060850:LIM-Homeodomain Proteins; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D009124:Muscle Proteins; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D014157:Transcription Factors; D004247:DNA; D002784:Cholesterol