Targeting LXRβ signaling using seaweed derived saringosterol attenuates atherosclerosis progression in mice

Moritz Nöthel (Bonn)1, L. Langkamp (Bonn)1, H. Blömer (Bonn)1, M. Bindmann (Bonn)1, M. T. Mulder (Rotterdam)2, T. Vanmierlo (Hasselt)3, D. Lütjohann (Bonn)4, S. Zimmer (Bonn)1, G. Nickenig (Bonn)1, 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 3 Department of Neuroscience, Biomedical Research Institute Hasselt, Belgien; 4Universitätsklinikum Bonn Institut für Klinische Chemie und Klinische Pharmakologie Bonn, Deutschland

 

Background:

LXR is a transcription factor that plays a crucial role in lipid metabolism, cholesterol homeostasis, and a variety of chronic inflammatory diseases. Targeting the liver-X-receptor (LXR) is a promising approach to attenuate atherogenesis. However, the clinical use of LXR agonists is limited due to fatty liver disease, which is an unwanted side effects of known LXR agonists. The seaweed-derived oxysterol, saringosterol, was recently identified as an agonist of the LXR that does not induce fatty liver disease. 

 

Methods:
In the present study, we investigated the effects of seaweed-derived saringosterol on atherosclerosis in ApoE-/- mice. Animals were treated with a high-fat, high-cholesterol (1,12%) diet for four weeks. The diet was either enriched with saringosterol (378 µg/d) or cellulose as placebo control. Liver and plasma concentrations of saringosterol were measured using gas chromatography-mass spectrometry with selected ion-monitoring. Histological sections through the aortic root were used to assess the atherosclerotic plaque burden and composition. En face staining of the descending thoracic aorta was performed to visualise the atherosclerotic plaque burden. The underlying molecular mechanisms were analysed in human monocytes after incubation with saringosterol. 

 

Results:

Treatment with a high-fat, high-cholesterol diet led to the formation of lipid-rich plaques in the aorta. En face staining revealed a significant reduction in plaque size in mice receiving saringosterol (saringosterol vs vehicle: 3.13 ± 0.76% vs 6.97 ± 0.70%; n = 5; p < 0.005). This finding was accompanied by a reduced atherosclerotic plaque burden in the aortic root (saringosterol vs vehicle 11,16 ± 1,32% vs 16,30 ± 1,178; n = 10-11; p < 0.01). 

Intriguingly, saringosterol did not induce fatty liver disease in our model but even decreased liver fatty acid content. 

In vitro, saringosterol increased the transcription of ABCA1 and ABCG1 in human monocytes. Pharmacological inhibition of LXR entirely abolished this effect. Additionally, saringosterol reduced the transcription of LDL receptor in human monocytes.

 

Conclusion:

Oral application of seaweed-derived saringosterol attenuates the development of atherosclerotic plaque in vivo. Our in vitro data suggest that LXR activation attenuates lipid deposition by upregulation of cholesterol efflux and by limiting cholesterol uptake in monocytes.

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