Moriyama Mitsuaki, Li Meng Xian, Kobayashi Keiko, Sinasac David S, Kannan Yukiko, Iijima Mikio, Horiuchi Masahisa, Tsui Lap-Chee, Tanaka Masashi, Nakamura Yoichi, Saheki Takeyori
Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan.
J Hepatol. 2006 May;44(5):930-8. doi: 10.1016/j.jhep.2005.09.018. Epub 2005 Nov 8.
BACKGROUND/AIMS: Mutations in SLC25A13, encoding the mitochondrial aspartate-glutamate carrier citrin, cause adult-onset type II citrullinemia (CTLN2) in humans. We have previously reported that although citrin-knockout (Ctrn-/-) mice fail to display symptoms of CTLN2, liver perfusion revealed a deficit in ureogenesis from ammonia accompanied by an increase in the perfusate lactate-to-pyruvate (L/P) ratio. The present study explores the effects of pyruvate, aspartate and citrate on improving the abnormalities observed in the Ctrn-/- liver.
We measured the rate of ureogenesis from ammonium chloride using the liver-perfusion system.
Pyruvate infusion lowered the L/P ratio and corrected the deficit in ureogenesis in the Ctrn-/- liver. This effect was found to be dose-dependent in both instances. Phenazine methosulfate, a cytosolic oxidant, also improved the rate of ureogenesis in the Ctrn-/- liver and led to a fall in the L/P ratio. The addition of aspartate or citrate did not change either the rate of ureogenesis or the L/P ratio in the Ctrn-/- liver.
Citrin deficiency disturbs urea synthesis primarily as a result of an elevated cytosolic NADH/NAD+ ratio owing to limited reoxidation of reducing equivalents. Clinically, pyruvate may have a therapeutic benefit for CTLN2 patients.
背景/目的：编码线粒体天冬氨酸-谷氨酸载体柑橘素的SLC25A13发生突变，可导致人类成年期II型瓜氨酸血症（CTLN2）。我们之前报道过，尽管柑橘素基因敲除（Ctrn-/-）小鼠未表现出CTLN2的症状，但肝脏灌注显示氨生成尿素的过程存在缺陷，同时灌注液中乳酸与丙酮酸（L/P）的比值升高。本研究探讨丙酮酸、天冬氨酸和柠檬酸对改善Ctrn-/-肝脏中观察到的异常情况的影响。
我们使用肝脏灌注系统测量氯化铵生成尿素的速率。
输注丙酮酸可降低Ctrn-/-肝脏的L/P比值，并纠正尿素生成缺陷。这两种情况均呈剂量依赖性。胞质氧化剂吩嗪硫酸甲酯也可提高Ctrn-/-肝脏中尿素生成的速率，并导致L/P比值下降。添加天冬氨酸或柠檬酸不会改变Ctrn-/-肝脏中尿素生成的速率或L/P比值。
柑橘素缺乏主要由于还原当量的再氧化受限导致胞质NADH/NAD+比值升高，从而干扰尿素合成。临床上，丙酮酸可能对CTLN2患者具有治疗益处。
