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Atherosclerosis and liver inflammation induced by increased dietary cholesterol intake: a combined transcriptomics and metabolomics analysis

Robert Kleemann12*, Lars Verschuren12, Marjan J van Erk3, Yuri Nikolsky4, Nicole HP Cnubben3, Elwin R Verheij3, Age K Smilde5, Henk FJ Hendriks3, Susanne Zadelaar1, Graham J Smith6, Valery Kaznacheev47, Tatiana Nikolskaya47, Anton Melnikov47, Eva Hurt-Camejo8, Jan van der Greef23, Ben van Ommen3 and Teake Kooistra1

Author Affiliations

1 Department of Vascular and Metabolic Diseases, TNO-Quality of Life, BioSciences, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, The Netherlands

2 Department of Vascular Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands

3 Department of Physiological Genomics, TNO-Quality of Life, BioSciences, Utrechtseweg 48, 3704 HE Zeist, The Netherlands

4 GeneGo Inc., Renaissance Drive, St Joseph, MI 49085, USA

5 Department of Analytical Research, TNO-Quality of Life, Quality and Safety, Utrechtseweg 48, 3704 HE Zeist, The Netherlands

6 AstraZeneca, CV&GI Research, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, UK

7 Vavilov Institute for General Genetics, Russian Academy of Science, Gubkin Street 3, 117809 Moscow, Russia

8 AstraZeneca CV&GI Research, 43183 Mölndal, Sweden

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Genome Biology 2007, 8:R200  doi:10.1186/gb-2007-8-9-r200

Published: 24 September 2007

Abstract

Background

Increased dietary cholesterol intake is associated with atherosclerosis. Atherosclerosis development requires a lipid and an inflammatory component. It is unclear where and how the inflammatory component develops. To assess the role of the liver in the evolution of inflammation, we treated ApoE*3Leiden mice with cholesterol-free (Con), low (LC; 0.25%) and high (HC; 1%) cholesterol diets, scored early atherosclerosis and profiled the (patho)physiological state of the liver using novel whole-genome and metabolome technologies.

Results

Whereas the Con diet did not induce early atherosclerosis, the LC diet did so but only mildly, and the HC diet induced it very strongly. With increasing dietary cholesterol intake, the liver switches from a resilient, adaptive state to an inflammatory, pro-atherosclerotic state. The liver absorbs moderate cholesterol stress (LC) mainly by adjusting metabolic and transport processes. This hepatic resilience is predominantly controlled by SREBP-1/-2, SP-1, RXR and PPARα. A further increase of dietary cholesterol stress (HC) additionally induces pro-inflammatory gene expression, including pro-atherosclerotic candidate genes. These HC-evoked changes occur via specific pro-inflammatory pathways involving specific transcriptional master regulators, some of which are established, others newly identified. Notably, several of these regulators control both lipid metabolism and inflammation, and thereby link the two processes.

Conclusion

With increasing dietary cholesterol intake the liver switches from a mainly resilient (LC) to a predominantly inflammatory (HC) state, which is associated with early lesion formation. Newly developed, functional systems biology tools allowed the identification of novel regulatory pathways and transcriptional regulators controlling both lipid metabolism and inflammatory responses, thereby providing a rationale for an interrelationship between the two processes.