Steineger H H, Sørensen H N, Tugwood J D, Skrede S, Spydevold O, Gautvik K M
Institute of Medical Biochemistry, University of Oslo, Blindern, Norway.
Eur J Biochem. 1994 Nov 1;225(3):967-74. doi: 10.1111/j.1432-1033.1994.0967b.x.
Fatty acids and the peroxisomal proliferator, 3-tetradecylthioacetic acid (TTA) stimulate transcription of peroxisomal beta-oxidation enzymes. Recently, we have shown that their actions are markedly modulated by dexamethasone and insulin which show synergistic and inhibitory effects, respectively. In this study, we describe the regulation of the peroxisomal proliferator-activated receptor (PPAR), a member of the steroid-hormone-receptor superfamily, in a similar manner by hormones and fatty acids, supporting the hypothesis that PPAR may act as a ligand-activated transcription factor. Northern-blot analysis of steady-state mRNA levels revealed three different specific transcripts for PPAR of 10.2, 4.6 and 1.8 kb, and the former two being regulated in hepatic tissue, hepatocytes and hepatoma cells. Dexamethasone produced a pronounced overall stimulatory effect (15.3-fold) in rat hepatocytes, while insulin blocked this action completely. Minor inductions of PPAR mRNA (up to twofold induction) were observed when different fatty acids were administrated alone. However, in combination with dexamethasone, additive or synergistic actions, mounting to 24-fold stimulation, were observed, while insulin always exerted an over-riding down-regulatory effect. In non-fasting rats receiving dexamethasone, elevation of serum insulin, a slight increase in serum free fatty acids accompanied by PPAR mRNA level increases of 2.4-fold and stimulation of liver peroxisomal acyl-CoA oxidase mRNA were observed. Our results suggest that PPAR mRNA expression is under strict hormonal control and that the fatty acids and hormones affect PPAR mRNA levels in a manner analogous to the regulation of the peroxisomal beta-oxidation enzymes. The PPAR gene-regulating unit apparently contains hormone-response elements (HRE) for dexamethasone and insulin, which are thus functionally important for PPAR transcription in liver cells, making a significant enhancement or inhibition of the physiological actions of fatty acids possible.
脂肪酸和过氧化物酶体增殖剂3-十四烷基硫代乙酸（TTA）可刺激过氧化物酶体β-氧化酶的转录。最近，我们发现它们的作用受到地塞米松和胰岛素的显著调节，地塞米松和胰岛素分别显示出协同和抑制作用。在本研究中，我们描述了类固醇激素受体超家族成员过氧化物酶体增殖物激活受体（PPAR）以类似方式受激素和脂肪酸调节，支持了PPAR可能作为配体激活转录因子的假说。对稳态mRNA水平的Northern印迹分析揭示了PPAR的三种不同特异性转录本，大小分别为10.2、4.6和1.8 kb，前两种在肝组织、肝细胞和肝癌细胞中受到调节。地塞米松在大鼠肝细胞中产生了明显的总体刺激作用（15.3倍），而胰岛素则完全阻断了这一作用。单独给予不同脂肪酸时，观察到PPAR mRNA有轻微诱导（最多两倍诱导）。然而，与地塞米松联合使用时，观察到有加性或协同作用，刺激倍数高达24倍，而胰岛素始终发挥主要的下调作用。在接受地塞米松的非禁食大鼠中，观察到血清胰岛素升高、血清游离脂肪酸略有增加，同时PPAR mRNA水平增加2.4倍，肝脏过氧化物酶体酰基辅酶A氧化酶mRNA受到刺激。我们的结果表明，PPAR mRNA表达受到严格的激素控制，脂肪酸和激素以类似于过氧化物酶体β-氧化酶调节的方式影响PPAR mRNA水平。PPAR基因调节单元显然含有地塞米松和胰岛素的激素反应元件（HRE），因此对肝细胞中PPAR转录在功能上很重要，使得脂肪酸的生理作用可能显著增强或受到抑制。
