Tous Mònica, Ferré Natàlia, Rull Anna, Marsillach Judit, Coll Blai, Alonso-Villaverde Carlos, Camps Jordi, Joven Jorge
Centre de Recerca Biomèdica, Institut de Recerca en Ciències de la Salut (IRCIS), Hospital Universitari de Sant Joan, Calle Sant Joan s/n, 43201-Reus, Spain.
Biochem Biophys Res Commun. 2006 Feb 24;340(4):1078-84. doi: 10.1016/j.bbrc.2005.12.109. Epub 2005 Dec 27.
In humans, hypercholesterolemia, steatohepatitis, and risk for arteriosclerosis are associated. Apolipoprotein E-deficient mice, a widely used animal model, show both arteriosclerosis and steatohepatitis in response to high-fat and cholesterol diets. We have found a relationship between these conditions and a higher mRNA aortic and hepatic monocyte chemoattractant protein-1 (mcp-1) gene expression. Both tissues respond in a similar way when dietary cholesterol is provided for a few weeks but differently if the conditions persist for a protracted period of time. After 8 months of treatment, the mcp-1 gene expression in the aorta continues increasing but in the liver decreases. This coincides with a significant increase in hepatic ppar-delta anti-inflammatory gene expression. Apparently, the arterial wall cannot prevent the deleterious effects of higher mcp-1 expression by increasing ppar-delta gene expression and the lesion progress. However, in the liver, the activation of anti-inflammatory genes may reduce the hepatic mcp-1 expression which significantly decreases the inflammatory response. This differential inflammatory gene expression in aorta and liver may support the idea that anti-inflammatory transcription factors are involved in the response to diet and inflammation. Therefore, the use of cholesterol-enriched diets should be carefully considered in the apolipoprotein E-deficient mice because they may trigger different stimuli and seriously hinder the interpretation of possible findings.
在人类中，高胆固醇血症、脂肪性肝炎和动脉粥样硬化风险是相关联的。载脂蛋白E缺陷小鼠是一种广泛使用的动物模型，在高脂和高胆固醇饮食条件下会出现动脉粥样硬化和脂肪性肝炎。我们发现这些病症与主动脉和肝脏中单核细胞趋化蛋白-1（MCP-1）基因的较高mRNA表达之间存在关联。当提供数周的膳食胆固醇时，这两种组织的反应相似，但如果这种情况持续较长时间，则反应不同。治疗8个月后，主动脉中的MCP-1基因表达持续增加，而肝脏中的则下降。这与肝脏中PPAR-δ抗炎基因表达的显著增加相吻合。显然，动脉壁无法通过增加PPAR-δ基因表达来阻止较高MCP-1表达的有害影响以及病变进展。然而，在肝脏中，抗炎基因的激活可能会降低肝脏中MCP-1的表达，从而显著降低炎症反应。主动脉和肝脏中这种不同的炎症基因表达可能支持这样一种观点，即抗炎转录因子参与了对饮食和炎症的反应。因此，在载脂蛋白E缺陷小鼠中应谨慎考虑使用富含胆固醇的饮食，因为它们可能引发不同的刺激并严重妨碍对可能结果的解读。
