Nutrigenomics Consortium, TI Food and Nutrition, Wageningen, the Netherlands.
Physiol Genomics. 2010 Mar 3;41(1):42-52. doi: 10.1152/physiolgenomics.00127.2009. Epub 2009 Dec 15.
Little is known about the role of the transcription factor peroxisome proliferator-activated receptor (PPAR) beta/delta in liver. Here we set out to better elucidate the function of PPARbeta/delta in liver by comparing the effect of PPARalpha and PPARbeta/delta deletion using whole genome transcriptional profiling and analysis of plasma and liver metabolites. In fed state, the number of genes altered by PPARalpha and PPARbeta/delta deletion was similar, whereas in fasted state the effect of PPARalpha deletion was much more pronounced, consistent with the pattern of gene expression of PPARalpha and PPARbeta/delta. Minor overlap was found between PPARalpha- and PPARbeta/delta-dependent gene regulation in liver. Pathways upregulated by PPARbeta/delta deletion were connected to innate immunity and inflammation. Pathways downregulated by PPARbeta/delta deletion included lipoprotein metabolism and various pathways related to glucose utilization, which correlated with elevated plasma glucose and triglycerides and reduced plasma cholesterol in PPARbeta/delta-/- mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPARbeta/delta target genes. In contrast to PPARalpha-/- mice, no changes in plasma free fatty acid, plasma beta-hydroxybutyrate, liver triglycerides, and liver glycogen were observed in PPARbeta/delta-/- mice. Our data indicate that PPARbeta/delta governs glucose utilization and lipoprotein metabolism and has an important anti-inflammatory role in liver. Overall, our analysis reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver.
关于转录因子过氧化物酶体增殖物激活受体 (PPAR)β/δ在肝脏中的作用知之甚少。在这里，我们通过全基因组转录谱分析和血浆及肝脏代谢物分析，比较了 PPARα和 PPARβ/δ缺失的影响，旨在更好地阐明 PPARβ/δ在肝脏中的功能。在进食状态下，PPARα和 PPARβ/δ缺失改变的基因数量相似，而在禁食状态下，PPARα缺失的影响更为明显，与 PPARα和 PPARβ/δ的基因表达模式一致。在肝脏中，PPARα 和 PPARβ/δ依赖性基因调控之间发现了较小的重叠。PPARβ/δ缺失上调的途径与先天免疫和炎症有关。PPARβ/δ缺失下调的途径包括脂蛋白代谢和与葡萄糖利用相关的各种途径，这与 PPARβ/δ-/-小鼠血浆葡萄糖和甘油三酯升高以及血浆胆固醇降低有关。可能导致这些代谢改变的下调基因包括 Pklr、Fbp1、Apoa4、Vldlr、Lipg 和 Pcsk9，它们可能代表新的 PPARβ/δ 靶基因。与 PPARα-/-小鼠不同，PPARβ/δ-/-小鼠的血浆游离脂肪酸、血浆β-羟丁酸、肝甘油三酯和肝糖原没有变化。我们的数据表明，PPARβ/δ 控制葡萄糖利用和脂蛋白代谢，并在肝脏中具有重要的抗炎作用。总的来说，我们的分析揭示了 PPARα 和 PPARβ/δ 在调节小鼠肝脏基因表达中的不同作用。
