Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1α
Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1α
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DOI：
10.1016/j.cell.2005.06.040
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发表时间：
2005-08-26
期刊：
影响因子：
64.5
通讯作者：
Spiegelman, BM
中科院分区：
文献类型：
--
作者：
Handschin, C;Lin, JD;Spiegelman, BM
诱发性肝卟啉症是一种遗传性的血红素生物合成酶的遗传性疾病。主要临床表现为神经精神症状的急性发作，常由药物、激素或禁食引起，并伴有尿中β-氨基酮戊酸(ALA)排泄增加。急性发作可以通过输注血红素和注射葡萄糖来治疗，但禁食的促发作用和葡萄糖的有益作用的机制尚不清楚。我们发现，肝脏血红素生物合成中的限速酶-5-氨基-乙酰丙酸合成酶(ALAS-1)受过氧化物酶体增殖物激活受体γ共激活物1α(PGC-1α)的调节。正如在急性发作中观察到的那样，通过腺病毒载体在小鼠体内升高PGC-1α增加了体内血红素前体的水平。在肝脏特异的PGC-1α基因敲除动物中，禁食诱导的ALAS-1丢失，同样的，致卟啉药物对血红素生物合成的失调能力也是如此。这些数据表明，PGC-1α将营养状态与血红素的生物合成和急性肝门脉症联系在一起。
Inducible hepatic porphyrias are inherited genetic disorders of enzymes of heme biosynthesis. The main clinical manifestations are acute attacks of neuropsychiatric symptoms frequently precipitated by drugs, hormones, or fasting, associated with increased urinary excretion of delta-aminolevulinic acid (ALA). Acute attacks are treated by heme infusion and glucose administration, but the mechanisms underlying the precipitating effects of fasting and the beneficial effects of glucose are unknown. We show that the rate-limiting enzyme in hepatic heme biosynthesis, 5-amino-levulinate synthase (ALAS-1), is regulated by the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha). Elevation of PGC-1 alpha in mice via adenoviral vectors increases the levels of heme precursors in vivo as observed in acute attacks. The induction of ALAS-1 by fasting is lost in liver-specific PGC-1 alpha knockout animals, as is the ability of porphyrogenic drugs to dysregulate heme biosynthesis. These data show that PGC-1 alpha links nutritional status to heme biosynthesis and acute hepatic porphyria.