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

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Author: Kleemann, R. · Verschuren, L. · Erk, M.J. van · Nikolsky, Y. · Cnubben, N.H.P. · Verheij, E.R. · Smilde, A.K. · Hendriks, H.F.J. · Zadelaar, A.S.M. · Smith, G.J. · Kaznacheev, V. · Nikolskaya, T. · Melnikov, A. · Hurt-Camejo, E. · Greef, J. van der · Ommen, B. van · Kooistra, T.
Institution: TNO Kwaliteit van Leven
Source:Genome Biology, 9, 8
Identifier: 240194
doi: doi:10.1186/gb-2007-8-9-r200
Article number: No.: R200
Keywords: Analytical research · Biomedical research · alanine aminotransferase · aspartate aminotransferase · cholesterol · endothelial leukocyte adhesion molecule 1 · gamma interferon · high density lipoprotein · hydroxymethylglutaryl coenzyme A reductase · immunoglobulin enhancer binding protein · interleukin 1 · low density lipoprotein · peroxisome proliferator activated receptor alpha · platelet derived growth factor · protein p53 · retinoid X receptor · retinoid X receptor alpha · serum amyloid A · Smad3 protein · STAT1 protein · STAT3 protein · STAT5 protein · sterol regulatory element binding protein 1 · sterol regulatory element binding protein 2 · transcription factor FKHR · transcription factor Sp1 · transcription factor YY1 · triacylglycerol · tumor necrosis factor alpha · very low density lipoprotein · alanine aminotransferase blood level · animal experiment · animal model · animal tissue · article · aspartate aminotransferase blood level · atherosclerosis · cholesterol blood level · cholesterol diet · cholesterol intake · controlled study · diet supplementation · female · gene control · genetic transcription · hepatitis · hypercholesterolemia · lipid metabolism · metabolomics · mouse · nonhuman · pathophysiology · protein blood level · stress · transcription regulation · transcriptomics · triacylglycerol blood level · upregulation · animal · biological model · diet · disease model · gene expression regulation · inflammation · liver · metabolism · pathology · systems biology · Mus · Animals · Atherosclerosis · Cholesterol, Dietary · Diet · Disease Models, Animal · Female · Gene Expression Regulation · Inflammation · Lipid Metabolism · Liver · Metabolism · Mice · Models, Biological · Systems Biology · Transcription, Genetic


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. ©2007 Kleemann et al.; licensee BioMed Central Ltd.