Guillén Natalia, Navarro María A, Arnal Carmen, Noone Enda, Arbonés-Mainar José M, Acín Sergio, Surra Joaquín C, Muniesa Pedro, Roche Helen M, Osada Jesús
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto Aragonés de Ciencias de la Salud (Universidad de Zaragoza-Salud del Gobierno de Aragón), Spain.
Physiol Genomics. 2009 May 13;37(3):187-98. doi: 10.1152/physiolgenomics.90339.2008. Epub 2009 Mar 3.
Trans-10, cis-12-conjugated linoleic acid (CLA)-enriched diets promote fatty liver in mice, while cis-9, trans-11-CLA ameliorates this effect, suggesting regulation of multiple genes. To test this hypothesis, apoE-deficient mice were fed a Western-type diet enriched with linoleic acid isomers, and their hepatic gene expression was analyzed with DNA microarrays. To provide an initial screening of candidate genes, only 12 with remarkably modified expression between both CLA isomers were considered and confirmed by quantitative RT-PCR. Additionally mRNA expression of 15 genes involved in lipid metabolism was also studied. Ten genes (Fsp27, Aqp4, Cd36, Ly6d, Scd1, Hsd3b5, Syt1, Cyp7b1, and Tff3) showed significant associations among their expressions and the degree of hepatic steatosis. Their involvement was also analyzed in other models of steatosis. In hyperhomocysteinemic mice lacking Cbs gene, only Fsp27, Cd36, Scd1, Syt1, and Hsd3b5 hepatic expressions were associated with steatosis. In apoE-deficient mice consuming olive-enriched diet displaying reduction of the fatty liver, only Fsp27 and Syt1 expressions were found associated. Using this strategy, we have shown that expression of these genes is highly associated with hepatic steatosis in a genetic disease such as Cbs deficiency and in two common situations such as Western diets containing CLA isomers or a Mediterranean-type diet.
The results highlight new processes involved in lipid handling in liver and will help to understand the complex human pathology providing new proteins and new strategies to cope with hepatic steatosis.
富含反式-10，顺式-12-共轭亚油酸（CLA）的饮食会促进小鼠患脂肪肝，而顺式-9，反式-11-CLA可改善这种作用，提示存在多个基因的调控。为验证该假说，给载脂蛋白E缺陷小鼠喂食富含亚油酸异构体的西式饮食，并用DNA微阵列分析其肝脏基因表达。为初步筛选候选基因，仅考虑了在两种CLA异构体之间表达有显著改变的12个基因，并通过定量RT-PCR进行了确认。此外，还研究了15个参与脂质代谢的基因的mRNA表达。10个基因（Fsp27、Aqp4、Cd36、Ly6d、Scd1、Hsd3b5、Syt1、Cyp7b1和Tff3）的表达与肝脂肪变性程度之间存在显著关联。还在其他脂肪变性模型中分析了它们的作用。在缺乏Cbs基因的高同型半胱氨酸血症小鼠中，只有Fsp27、Cd36、Scd1、Syt1和Hsd3b5的肝脏表达与脂肪变性有关。在食用富含橄榄油饮食且脂肪肝减轻的载脂蛋白E缺陷小鼠中，仅发现Fsp27和Syt1的表达有关联。使用该策略，我们已表明，在诸如Cbs缺乏这样的遗传疾病以及两种常见情况（如含有CLA异构体的西式饮食或地中海式饮食）中，这些基因的表达与肝脂肪变性高度相关。
这些结果突出了肝脏脂质处理中涉及的新过程，将有助于理解复杂的人类病理学，为应对肝脂肪变性提供新的蛋白质和新策略。
