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

被引：184

作者：

Kleemann, Robert ^{[1
,2
]}

Verschuren, Lars ^{[1
,2
]}

van Erk, Marjan J. ^{[3
]}

Nikolsky, Yuri ^{[4
]}

Cnubben, Nicole H. P. ^{[3
]}

Verheij, Elwin R. ^{[3
]}

Smilde, Age K. ^{[5
]}

Hendriks, Henk F. J. ^{[3
]}

Zadelaar, Susanne ^{[1
]}

Smith, Graham J. ^{[6
]}

Kaznacheev, Valery ^{[4
,7
]}

Nikolskaya, Tatiana ^{[4
,7
]}

Melnikov, Anton ^{[4
,7
]}

Hurt-Camejo, Eva ^{[8
]}

van der Greef, Jan ^{[2
,3
]}

van Ommen, Ben ^{[3
]}

Kooistra, Teake ^{[1
]}

机构：

[1] TNO Qual Life BioSci, Gaubius Lab, Dept Vasc & Metab Dis, NL-2333 CK Leiden, Netherlands

[2] Leiden Univ, Med Ctr, Dept Vasc Surg, NL-2300 RC Leiden, Netherlands

[3] TNO Qual Life BioSci, Dept Physiol Genom, NL-3704 HE Zeist, Netherlands

[4] GeneGo Inc, St Joseph, MI 49085 USA

[5] TNO Qual Life Qual & Safety, Dept Analyt Res, NL-3704 HE Zeist, Netherlands

[6] AstraZeneca, CV&GI Res, Macclesfield SK10 2NA, Cheshire, England

[7] Russian Acad Sci, Vavilov Inst Gen Genet, Moscow 117809, Russia

[8] AstraZeneca CV&GI Res, S-43183 Molndal, Sweden

来源：

GENOME BIOLOGY | 2007年 / 8卷 / 09期

关键词：

D O I：

10.1186/gb-2007-8-9-r200

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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 PPAR alpha. 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.

引用

页数：16

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