Skvorak Kristen J, Hager Elizabeth J, Arning Erland, Bottiglieri Teodoro, Paul Harbhajan S, Strom Stephen C, Homanics Gregg E, Sun Qin, Jansen Erwin E W, Jakobs Cornelis, Zinnanti William J, Gibson K Michael
Department of Pediatrics, University of Pittsburgh School of Medicine, USA; Children's Hospital of Pittsburgh of UPMC, USA.
Biochim Biophys Acta. 2009 Oct;1792(10):1004-10. doi: 10.1016/j.bbadis.2009.08.006. Epub 2009 Aug 19.
Skvorak et al. [1] demonstrated the therapeutic efficacy of HTx in a murine model of iMSUD, confirming significant metabolic improvement and survival. To determine the effect of HTx on extrahepatic organs, we examined the metabolic effects of HTx in brain from iMSUD animals. Amino acid analysis revealed that HTx corrected increased ornithine, partially corrected depleted glutamine, and revealed a trend toward alloisoleucine correction. For amino acid and monoamine neurotransmitters, decreased GABA was partially corrected with HTx, while the l-histidine dipeptide of GABA, homocarnosine, was decreased in iMSUD mice and hypercorrected following HTx. Elevated branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in MSUD can deplete brain tyrosine and tryptophan (the precursors of monoamine neurotransmitters, dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT)) through competition via the large neutral amino acid transporter. HTx corrected decreased DA levels and the DA metabolite, 3-methoxytyramine, and partially corrected the DA intermediate 3,4-dihydroxyphenylacetate (DOPAC) and 5-HT levels, despite normal tyrosine and tryptophan levels in iMSUD mouse brain. We further observed enhanced intracellular turnover of both DA and 5-HT in iMSUD mouse brain, both of which partially corrected with HTx. Our results suggest new pathomechanisms of neurotransmitter metabolism in this disorder and support the therapeutic relevance of HTx in iMSUD mice, while providing proof-of-principle that HTx has corrective potential in extrahepatic organs.
斯克沃拉克等人[1]在iMSUD的小鼠模型中证实了肝移植（HTx）的治疗效果，确认其能显著改善代谢并提高生存率。为了确定HTx对肝外器官的影响，我们检测了iMSUD动物大脑中HTx的代谢作用。氨基酸分析显示，HTx纠正了鸟氨酸升高的情况，部分纠正了谷氨酰胺的消耗，并显示出异亮氨酸纠正的趋势。对于氨基酸和单胺类神经递质，HTx部分纠正了γ-氨基丁酸（GABA）的降低，而GABA的L-组氨酸二肽即高肌肽，在iMSUD小鼠中降低，HTx后过度纠正。MSUD中升高的支链氨基酸（BCAA；亮氨酸、异亮氨酸和缬氨酸）可通过大中性氨基酸转运体的竞争消耗大脑中的酪氨酸和色氨酸（单胺类神经递质多巴胺（DA）和5-羟色胺（5-HT）的前体）。尽管iMSUD小鼠大脑中的酪氨酸和色氨酸水平正常，但HTx纠正了降低的DA水平和DA代谢物3-甲氧基酪胺，并部分纠正了DA中间体3,4-二羟基苯乙酸（DOPAC）和5-HT水平。我们进一步观察到iMSUD小鼠大脑中DA和5-HT的细胞内周转率增强，两者均被HTx部分纠正。我们的结果提示了这种疾病中神经递质代谢的新发病机制，支持了HTx对iMSUD小鼠的治疗相关性，同时提供了原理证明，即HTx对肝外器官具有纠正潜力。
