LXRβ signalling is a key mediator in the pathogenesis of aortic valve stenosis

Moritz Nöthel (Bonn)1, A. Schmidt (Bonn)1, H. Blömer (Bonn)1, M. T. Mulder (Rotterdam)2, T. Vanmierlo (Hasselt)3, S. Friedrichs (Bonn)4, G. Voortman (Rotterdam)2, P. R. Goody (Bonn)1, S. Zimmer (Bonn)1, G. Nickenig (Bonn)1, D. Lütjohann (Bonn)4, J. Jehle (Bonn)1

1Universitätsklinikum Bonn Medizinische Klinik und Poliklinik II Bonn, Deutschland; 2Erasmus University Medical Center Department of Internal Medicine, Section Pharmacology and Vascular Medicine Rotterdam, Niederlande; 3Hasselt University Department of Neuroscience, Biomedical Research Institute Hasselt, Belgien; 4Universitätsklinikum Bonn Institut für Klinische Chemie und Klinische Pharmakologie Bonn, Deutschland



LXRβ is a transcription factor that plays a crucial role in lipid metabolism, specifically in cholesterol homeostasis and a variety of chronic inflammatory diseases. However, its impact on aortic valve stenosis (AS) is unknown. The seaweed-derived oxysterol, saringosterol, was recently identified as an agonist of the liver-X-receptor β (LXRβ).



In the present study, we collected tissue samples from aortic valves of patients with AS or aortic regurgitation (AR). Transcriptomics were performed and gene ontology (GO) analysis was used to determine pathways and genes that are relevant to AS.

In vivo, mice received a wire-induced aortic valve stenosis and were either fed a diet supplemented with saringosterol or vehicle. In addition, the sterol concentrations in liver, bile and plasma were measured using gas chromatography-mass spectrometry with selected ion-monitoring. The expression of LXRβ-regulated genes in tissue samples was analysed by qPCR. The haemodynamic characteristics were assessed by echocardiography, whereas the thickness and composition of the aortic valve was assessed by histological staining.

Human aortic valve interstitial cells (VIC) were used to investigate the underlying molecular mechanisms of saringosterol treatment.



We observed several differentially regulated GO terms in AS compared to AR, with the most prominent one being GO:0046890 - regulation of lipid biosynthetic process (Score 1.91; p.adjust = 0.031; p-value < 0.001). A database analysis (DB-String) revealed that a relevant fration of the included genes were related to LXRβ, while the remaining genes did not exhibit any significant clustering.

In vivo treatment with saringosterol led to a significant accumulation of saringosterol in liver tissue (saringosterol vs. vehicle: 31.82 ± 5.03 ng/mg vs. 1.86 ± 0.04 ng/mg; n = 10–11; p < 0.0001). Correspondingly, an upregulation of downstream-targets of LXR was observed. 

Of particular interest, we detected a distinct alteration in hepatic cholesterol biosynthesis, shifting towards the Bloch pathway, even though there was no difference in total cholesterol concentration in the liver and serum.

Six weeks after the wire injury, the peak velocity of the aortic valve increased, indicating AS. This effect was attenuated in mice receiving saringosterol (saringosterol vs. vehicle: 1867 ± 112.6 mm/s vs. 2246 ± 118.1 mm/s; n = 10-11; p < 0.05). This finding was accompanied by a reduction in valve area by H.E.-staining (saringosterol vs. vehicle: 0.119 ± 0.013 mm2 vs. 0.163 ± 0.011 mm2; n = 10–11; p < 0.05). 

In vitro, saringosterol dose-dependently increased the transcription of ABCA1 and ABCG1 in VIC. This effect was completely abolished by pharmacological inhibition of the LXR receptor with its antagonist GSK2033. Furthermore, saringosterol reduced the expression of RUNX-2 and ACTA-2 in procalcifing medium, suggesting less differentiation into osteoblastic and myofibroblastic phenotypes, respectively. 



In this study, we could show that a dysregulation of LXRβ is involved in the development of aortic valve stenosis in human samples. Saringosterol activates LXRβ and alters hepatic cholesterol metabolism without causing LXR-associated side effects. Furthermore, increased LXRβ activity has a protective effect on the development of aortic valve stenosis in mice. Mechanistically, this can be explained by an increased cellular cholesterol efflux and a reduced adverse differentiation of VIC.

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