Effect of a High Phosphorus Diet on Hepatic Gene Expressions in Rat

A high phosphorus (HP) diet causes disorders of renal function, bone metabolism, and vascular function. We previously demonstrated that DNA microarray analysis is an appropriate method to comprehensively evaluate the effects of a HP diet on kidney dysfunction such as calcification, fibrillization, and inflammation. We reported that type IIb sodium-dependent phosphate transporter is significantly up-regulated in this context. In the present study, we performed DNA microarray analysis to investigate the effects of a HP diet on the liver, which plays a pivotal role in energy metabolism. DNA microarray analysis was performed with total RNA isolated from the livers of rats fed a control diet (containing 0.3% phosphorus) or a HP diet (containing 1.2% phosphorus). Gene Ontology analysis of differentially expressed genes (DEGs) revealed that the HP diet induced down-regulation of genes involved in hepatic amino acid catabolism and lipogenesis, while genes related to fatty acid ß-oxidation process were up-regulated. Although genes related to fatty acid biosynthesis were down-regulated in HP diet-fed rats, genes important for the elongation and desaturation reactions of omega-3 and -6 fatty acids were up-regulated. Concentrations of hepatic arachidonic acid and eicosapentaenoic acid were increased in HP diet-fed rats. These essential fatty acids activate peroxisome proliferator-activated receptor alpha (PPARa), a transcription factor for fatty acid ß-oxidation. Evaluation of the upstream regulators of DEGs using Ingenuity Pathway Analysis indicated that PPARa was activated in the livers of HP diet-fed rats. Furthermore, the serum concentration of fibroblast growth factor 21, a hormone secreted from the liver that promotes fatty acid utilization in adipose tissue as a PPARa target gene, was higher (p = 0.054) in HP diet-fed rats than in control diet-fed rats. These data suggest that a HP diet enhances energy expenditure through the utilization of free fatty acids released via lipolysis of white adipose tissue.高磷（HP）饮食可引发肾功能、骨代谢与血管功能紊乱。我们此前已证实，DNA微阵列（DNA microarray）分析是全面评估高磷饮食对肾功能障碍（如钙化、纤维形成、炎症）影响的适宜方法，且已报道在此情境下IIb型钠依赖性磷酸盐转运蛋白的表达显著上调。本研究中，我们通过DNA微阵列分析探究了高磷饮食对在能量代谢中发挥关键作用的肝脏的影响。实验以喂食对照日粮（磷含量0.3%）或高磷日粮（磷含量1.2%）的大鼠肝脏提取的总RNA开展DNA微阵列检测。对差异表达基因（differentially expressed genes, DEGs）的基因本体论（Gene Ontology）分析结果显示，高磷饮食可诱导肝脏氨基酸分解代谢与脂肪生成相关基因的表达下调，而与脂肪酸β-氧化过程相关的基因表达则会上调。尽管高磷饮食喂食的大鼠体内脂肪酸生物合成相关基因表达下调，但参与ω-3与ω-6脂肪酸延伸及去饱和反应的关键基因表达却出现上调。高磷饮食喂食的大鼠肝脏中，花生四烯酸与二十碳五烯酸的浓度有所升高。这类必需脂肪酸可激活过氧化物酶体增殖物激活受体α（peroxisome proliferator-activated receptor alpha, PPARα）——一种调控脂肪酸β-氧化的转录因子。通过Ingenuity通路分析（Ingenuity Pathway Analysis）对差异表达基因的上游调控因子进行评估，结果显示高磷饮食喂食的大鼠肝脏中PPARα被激活。此外，作为PPARα靶基因的成纤维细胞生长因子21（fibroblast growth factor 21, FGF21）是肝脏分泌的、可促进脂肪组织脂肪酸利用的激素，其血清浓度在高磷饮食喂食组中高于对照组（p=0.054）。上述数据表明，高磷饮食可通过促进白色脂肪组织脂解释放游离脂肪酸，提升能量消耗。