Vogel Kara R, Arning Erland, Bottiglieri Teodoro, Gibson K Michael
Division of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Pharmaceutical and Biomedical Sciences Building, Room 347, 412 E. Spokane Falls Blvd, Spokane, WA, 99204, USA.
Kimberly H. Courtwright and Joseph W. Summers Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX, USA.
J Inherit Metab Dis. 2017 Mar;40(2):227-235. doi: 10.1007/s10545-016-9984-3. Epub 2016 Oct 19.
The mainstay of therapy for phenylketonuria (PKU) remains dietary protein restriction. Developmental and neurocognitive outcomes for patients, however, remain suboptimal. We tested the hypothesis that mice with PKU receiving protein-restricted diets would reveal disruptions of brain amino acids that shed light on these neurocognitive deficits.
Phenylalanine hydroxylase-deficient (PKU) mice and parallel controls (both wild-type and heterozygous) were fed custom diets containing 18, 6, and 4 % protein for 3 weeks, after which tissues (brain, liver, sera) were collected for amino acid analysis profiling.
Phenylalanine (phe) was increased in all tissues (p < 0.0001) of PKU mice and improved with protein restriction. In sera, decreased tyrosine (p < 0.01) was corrected (defined as not significantly different from the level in control mice receiving 18 % chow) with protein restriction, whereas protein restriction significantly increased many other amino acids. A similar trend for increased amino acid levels with protein restriction was also observed in liver. In brain, the effects of protein restriction on large neutral amino acids (LNAAs) were variable, with some deficit correction (threonine, methionine, glutamine) and no correction of tyrosine under any dietary paradigm. Protein restriction (4 % diet) in PKU mice significantly decreased lysine, arginine, taurine, glutamate, asparagine, and serine which had been comparable to control mice under 18 % protein intake.
Depletion of taurine, glutamate, and serine in the brain of PKU mice with dietary protein restriction may provide new insight into neurocognitive deficits of PKU.
苯丙酮尿症（PKU）的主要治疗方法仍然是限制饮食中的蛋白质摄入。然而，患者的发育和神经认知结果仍不尽人意。我们检验了这样一个假设，即接受蛋白质限制饮食的苯丙酮尿症小鼠会出现脑氨基酸紊乱，从而揭示这些神经认知缺陷。
给苯丙氨酸羟化酶缺陷（PKU）小鼠以及平行对照组（野生型和杂合子）喂食含18%、6%和4%蛋白质的定制饮食，持续3周，之后收集组织（脑、肝脏、血清）进行氨基酸分析谱测定。
PKU小鼠的所有组织中苯丙氨酸（phe）均升高（p < 0.0001），且随着蛋白质限制而改善。在血清中，蛋白质限制纠正了酪氨酸降低的情况（p < 0.01）（定义为与接受18%普通饲料的对照小鼠水平无显著差异），而蛋白质限制显著增加了许多其他氨基酸。在肝脏中也观察到了蛋白质限制使氨基酸水平升高的类似趋势。在脑中，蛋白质限制对大中性氨基酸（LNAAs）的影响各不相同，在任何饮食模式下，一些氨基酸缺陷得到纠正（苏氨酸、蛋氨酸、谷氨酰胺），而酪氨酸未得到纠正。PKU小鼠的蛋白质限制（4%饮食）显著降低了赖氨酸、精氨酸、牛磺酸、谷氨酸、天冬酰胺和丝氨酸，这些氨基酸在蛋白质摄入量为18%时与对照小鼠相当。
饮食蛋白质限制的PKU小鼠脑中牛磺酸、谷氨酸和丝氨酸的消耗可能为苯丙酮尿症的神经认知缺陷提供新的见解。
