Acute Intermittent Porphyria (AIP), an autosomal dominant hepatic disorder, results from hydroxymethylbilane synthase (HMBS) mutations that decrease the encoded enzymatic activity, thereby predisposing patients to life-threatening acute neurovisceral attacks. The ~1% penetrance of AIP suggests that other genetic factors modulate the onset and severity of the acute attacks. Here, we characterized the hepatic transcriptomic response to phenobarbital (PB) administration in AIP mice, which mimics the biochemical attacks of AIP. At baseline, the mRNA profiles of 14,138 hepatic genes prior to treatment were remarkably similar between AIP and the congenic wild-type (WT) mice. After PB treatment (~120 mg/kg x 3d), 1347 and 1120 genes in AIP mice and 422 and 404 genes in WT mice were uniquely up- and down-regulated, respectively, at a False Discovery Rate < 0.05. As expected, the ALAS1 expression increased 4.5-fold and 15.9-fold in the WT and AIP mice, respectively. ALA-dehydrogenase also was induced ~1.7-fold in PB-induced AIP mice, but was unchanged in PB-induced WT mice. There was no statistically significant difference in the overall expression of 155 hepatic cytochrome P450 enzymes, although Cyp2c40, Cyp2c68, Cyp2c69, Mgst3 were upregulated only in PB-induced AIP mice (>1.9-fold) and Cyp21a1 was upregulated only in PB-induced WT mice (>9-fold). Notably, the genes differentially expressed in induced AIP mice were enriched in circadian rhythm, mitochondria biogenesis and electron transport, suggesting these pathways were involved in AIP mice responding to PB treatment. These results advance our understanding of the hepatic metabolic changes in PB-induced AIP mice and have implications in the pathogenesis of AIP acute attacks.

中文翻译：

---

AIP小鼠苯巴比妥诱导后肝转录组的特征。

急性间歇性卟啉症（AIP）是常染色体显性肝病，是由羟甲基胆烷合酶（HMBS）突变导致的，该突变降低了编码的酶活性，从而使患者容易遭受威胁生命的急性神经内脏攻击。AIP的〜1％渗透率表明其他遗传因素可调节急性发作的发作和严重程度。在这里，我们表征了在AIP小鼠中对苯巴比妥（PB）给药的肝转录反应，其模仿了AIP的生化攻击。在基线时，AIP和同基因野生型（WT）小鼠之间治疗前的14138个肝基因的mRNA谱非常相似。PB处理（〜120 mg / kg x 3d）后，AIP小鼠中的1347和1120基因以及WT小鼠中的422和404基因分别被独特地上调和下调，错误发现率<0.05。如预期的那样，ALAS1表达在WT和AIP小鼠中分别增加了4.5倍和15.9倍。在PB诱导的AIP小鼠中，ALA脱氢酶也被诱导了约1.7倍，而在PB诱导的WT小鼠中，ALA脱氢酶没有变化。155种肝细胞色素P450酶的总体表达没有统计学上的显着差异，尽管Cyp2c40，Cyp2c68，Cyp2c69，Mgst3仅在PB诱导的AIP小鼠中上调（> 1.9倍），而Cyp21a1仅在PB诱导的WT中上调小鼠（> 9倍）。值得注意的是，在诱导的AIP小鼠中差异表达的基因在昼夜节律，线粒体生物发生和电子转运中均富集，表明这些途径参与了PB处理的AIP小鼠。