PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis
PPARα via HNF4α regulates the expression of genes encoding hepatic amino acid catabolizing enzymes to maintain metabolic homeostasis
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DOI：
10.1007/s12263-014-0452-0
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发表时间：
2015-03-01
影响因子：
3.5
通讯作者：
Tovar, Armando R.
中科院分区：
文献类型：
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作者：
Contreras, Alejandra V.;Rangel-Escareno, Claudia;Tovar, Armando R.
肝脏是参与氨基酸（AA）代谢的主要器官，AA由氨基酸分解代谢酶（AACE）氧化。过氧化物酶体增殖物激活受体-α（PPAR α）刺激脂肪酸β-氧化，有证据表明，它可以在能量燃料转换期间调节肝脏AA氧化。为了了解PPARalpha对AA catalysts的调节作用和机制，我们研究了PPara敲除小鼠的代谢和分子适应。通过体外和体内研究检查了PPAR α对AA代谢的作用。在野生型和Ppara基因缺失小鼠中，喂食浓度增加的膳食蛋白质/碳水化合物比例，我们测量代谢参数，并通过微阵列分析、组织学和Western印迹分析肝脏。进行功能富集分析、EMSA和基因报告基因测定。PPara基因敲除小鼠肝脏中AACE表达增加，影响AA、脂质和碳水化合物代谢。PPara基因敲除小鼠对高蛋白/低碳水化合物饮食的反应是胰高血糖素/胰岛素比率增加（7.2倍）、血清尿素升高（73.1%）、身体蛋白含量降低（19.7%）和几种血清AA降低。差异表达基因的功能网络表明，AACE表达的变化受到PPAR α和HNF 4 α之间相互关系的调节。我们的数据表明，AACE的表达是通过减少HNF 4 α转录活性，如在丝氨酸脱氢酶基因启动子中观察到的，通过PPAR α下调。PPAR α通过HNF 4 α通过下调参与氨基酸催化剂的基因来维持身体蛋白质代谢稳态，以保持身体氮。
The liver is the main organ involved in the metabolism of amino acids (AA), which are oxidized by amino acid catabolizing enzymes (AACE). Peroxisome proliferator-activated receptor-alpha (PPAR alpha) stimulates fatty acid beta-oxidation, and there is evidence that it can modulate hepatic AA oxidation during the transition of energy fuels. To understand the role and mechanism of PPAR alpha's regulation of AA catabolism, the metabolic and molecular adaptations of Ppara-null mice were studied. The role of PPAR alpha on AA metabolism was examined by in vitro and in vivo studies. In wild-type and Ppara-null mice, fed increasing concentrations of the dietary protein/carbohydrate ratio, we measured metabolic parameters, and livers were analyzed by microarray analysis, histology and Western blot. Functional enrichment analysis, EMSA and gene reporter assays were performed. Ppara-null mice presented increased expression of AACE in liver affecting AA, lipid and carbohydrate metabolism. Ppara-null mice had increased glucagon/ insulin ratio (7.2-fold), higher serum urea (73.1 %), lower body protein content (19.7 %) and decreased several serum AA in response to a high-protein/low-carbohydrate diet. A functional network of differentially expressed genes, suggested that changes in the expression of AACE were regulated by an interrelationship between PPAR alpha and HNF4 alpha. Our data indicated that the expression of AACE is down-regulated through PPAR alpha by attenuating HNF4 alpha transcriptional activity as observed in the serine dehydratase gene promoter. PPAR alpha via HNF4 alpha maintains body protein metabolic homeostasis by down-regulating genes involved in amino acid catabolism for preserving body nitrogen.