Atherosclerosis and liver inflammation induced by increased dietary cholesterol intake: A combined transcriptomics and metabolomics analysis
article
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.
Topics
Analytical researchBiomedical researchalanine aminotransferaseaspartate aminotransferasecholesterolendothelial leukocyte adhesion molecule 1gamma interferonhigh density lipoproteinhydroxymethylglutaryl coenzyme A reductaseimmunoglobulin enhancer binding proteininterleukin 1low density lipoproteinperoxisome proliferator activated receptor alphaplatelet derived growth factorprotein p53retinoid X receptorretinoid X receptor alphaserum amyloid ASmad3 proteinSTAT1 proteinSTAT3 proteinSTAT5 proteinsterol regulatory element binding protein 1sterol regulatory element binding protein 2transcription factor FKHRtranscription factor Sp1transcription factor YY1triacylglyceroltumor necrosis factor alphavery low density lipoproteinalanine aminotransferase blood levelanimal experimentanimal modelanimal tissuearticleaspartate aminotransferase blood levelatherosclerosischolesterol blood levelcholesterol dietcholesterol intakecontrolled studydiet supplementationfemalegene controlgenetic transcriptionhepatitishypercholesterolemialipid metabolismmetabolomicsmousenonhumanpathophysiologyprotein blood levelstresstranscription regulationtranscriptomicstriacylglycerol blood levelupregulationanimalbiological modeldietdisease modelgene expression regulationinflammationlivermetabolismpathologysystems biologyMusAnimalsAtherosclerosisCholesterol, DietaryDietDisease Models, AnimalFemaleGene Expression RegulationInflammationLipid MetabolismLiverMetabolismMiceModels, BiologicalSystems BiologyTranscription, Genetic
TNO Identifier
240194
ISSN
14747596
Source
Genome Biology, 8(9)
Article nr.
No.: R200
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