Atherosclerosis and liver inflammation induced by increased dietary cholesterol intake: a combined transcriptomics and metabolomics analysis.
Atherosclerosis and liver inflammation induced by increased dietary cholesterol intake: a combined transcriptomics and metabolomics analysis.
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DOI：
10.1186/gb-2007-8-9-r200
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发表时间：
2007
期刊：
影响因子：
12.3
通讯作者：
Kooistra T
中科院分区：
文献类型：
--
作者：
Kleemann R;Verschuren L;van Erk MJ;Nikolsky Y;Cnubben NH;Verheij ER;Smilde AK;Hendriks HF;Zadelaar S;Smith GJ;Kaznacheev V;Nikolskaya T;Melnikov A;Hurt-Camejo E;van der Greef J;van Ommen B;Kooistra T
随着饮食中胆固醇摄入量的增加，肝脏从主要有弹性的状态转变为以炎症为主的状态，这与早期病变的形成有关。饮食中胆固醇摄入量增加与动脉粥样硬化有关。动脉粥样硬化的发展需要一种脂质和一种炎症成分。目前尚不清楚炎症成分在哪里以及如何发展。为了评估肝脏在炎症演变中的作用，我们用无胆固醇(Con)、低胆固醇(LC；0.25%)和高胆固醇(HC；1%)的饮食治疗ApoE*3莱顿小鼠，对早期动脉粥样硬化进行评分，并使用新的全基因组和代谢组技术描述肝脏的(病理)生理状态。而CON饮食不会导致早期动脉粥样硬化，LC饮食会导致动脉粥样硬化，但程度较轻，而HC饮食会非常强烈地诱导动脉粥样硬化。随着饮食中胆固醇摄入量的增加，肝脏从弹性、适应性状态切换到炎症性、有利于动脉粥样硬化的状态。肝脏主要通过调节代谢和运输过程来吸收适度的胆固醇应激(LC)。这种肝脏弹性主要由SREBP-1/-2、SP-1、RXR和PPARα控制。膳食胆固醇应激(HC)的进一步增加还会诱导促炎基因的表达，包括促动脉粥样硬化候选基因。这些由HC引起的变化通过特定的促炎途径发生，涉及特定的转录主调控因子，其中一些已经确定，另一些是新发现的。值得注意的是，其中几种调节剂同时控制脂肪代谢和炎症，从而将这两个过程联系在一起。随着膳食胆固醇摄入量的增加，肝脏从主要有弹性的(LC)状态转变为以炎症(HC)为主的状态，这与早期病变的形成有关。新开发的功能系统生物学工具可以识别控制脂质代谢和炎症反应的新的调控途径和转录调节因子，从而为这两个过程之间的相互关系提供了理论基础。
With increasing dietary cholesterol intake the liver switches from a mainly resilient to a predominantly inflammatory state, which is associated with early lesion formation. 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. 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. 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.