The effects of a low protein diet on amino acids and enzymes in the serine synthesis pathway in mice

l-Serine is required for cellular and tissue growth and is particularly important in the immature brain where it acts as a crucial neurotrophic factor. In this study, the levels of amino acids and enzymes in the l-serine biosynthetic pathway were examined in the forebrain, cerebellum, liver, and kidney after the exposure of mice to protein-restricted diets. The levels of l-serine, d-serine, and l-serine-O-phosphate were quantified by HPLC and quantitative Western blotting was used to measure changes in protein levels of five enzymes in the pathway. The l-serine biosynthetic enzyme phosphoserine phosphatase was strongly upregulated, while the serine degradative enzymes serine racemase and serine dehydratase were downregulated in the livers and kidneys of mice fed low (6%) or very low (2%) protein diets for 2 weeks compared with mice fed a normal diet (18% protein). No changes in these enzymes were seen in the brain. The levels of l-serine increased in the livers of mice fed 2% protein; in contrast, d-serine levels were reduced below the limit of detection in the livers of mice given either the 6 or 2% diets. d-Serine is a co-agonist at the NMDA class of glutamate receptors; no alterations in NMDA-R1 subunit expression were observed in liver or brain after protein restriction. These findings demonstrate that the expression of l-serine synthetic and degradative enzymes display reciprocal changes in the liver and kidney to increase l-serine and decrease d-serine levels under conditions of protein restriction, and that the brain is insulated from such changes.