title: Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI).
abstract: Lysinuric protein intolerance (LPI [MIM 222700]) is an aminoaciduria with defective transport of cationic amino acids in epithelial cells in the small intestine and proximal kidney tubules due to mutations in the SLC7A7 gene. LPI is characterized by protein malnutrition, failure to thrive and hyperammonemia. Many patients also suffer from combined hyperlipidemia and chronic kidney disease (CKD) with an unknown etiology.
  
  
  
  Here, we studied the plasma metabolomes of the Finnish LPI patients (n=26) and healthy control individuals (n=19) using a targeted platform for analysis of amino acids as well as two analytical platforms with comprehensive coverage of molecular lipids and polar metabolites.
  
  
  
  Our results demonstrated that LPI patients have a dichotomy of amino acid profiles, with both decreased essential and increased non-essential amino acids. Altered levels of metabolites participating in pathways such as sugar, energy, amino acid and lipid metabolism were observed. Furthermore, of these metabolites, myo-inositol, threonic acid, 2,5-furandicarboxylic acid, galactaric acid, 4-hydroxyphenylacetic acid, indole-3-acetic acid and beta-aminoisobutyric acid associated significantly (P<0.001) with the CKD status. Lipid analysis showed reduced levels of phosphatidylcholines and elevated levels of triacylglycerols, of which long-chain triacylglycerols associated (P<0.01) with CKD.
  
  
  
  This study revealed an amino acid imbalance affecting the basic cellular metabolism, disturbances in plasma lipid composition suggesting hepatic steatosis and fibrosis and novel metabolites correlating with CKD in LPI. In addition, the CKD-associated metabolite profile along with increased nitrite plasma levels suggests that LPI may be characterized by increased oxidative stress and apoptosis, altered microbial metabolism in the intestine and uremic toxicity.
authors: Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. Electronic address: johanna.kurko@utu.fi.
authors: Johanna
authors: J
authors: Kurko
authors: Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. Electronic address: maaria.tringham@utu.fi.
authors: Maaria
authors: M
authors: Tringham
authors: Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland; Department of Clinical Genetics, Turku University Hospital, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: laura.tanner@utu.fi.
authors: Laura
authors: L
authors: Tanner
authors: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: kirsti.nanto-salonen@tyks.fi.
authors: Kirsti
authors: K
authors: Näntö-Salonen
authors: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: mari.vaha-makila@utu.fi.
authors: Mari
authors: M
authors: Vähä-Mäkilä
authors: VTT Technical Research Centre of Finland, Tietotie 2, P.O. Boxs 1000, Espoo 02044 VTT, Finland. Electronic address: heli.nygren@vtt.fi.
authors: Heli
authors: H
authors: Nygren
authors: Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, P.O. Boxs 56, Helsinki 00014, Finland. Electronic address: paivi.poho@helsinki.fi.
authors: Päivi
authors: P
authors: Pöhö
authors: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Tykistökatu 6, 20520 Turku, Finland. Electronic address: nlietzen@btk.fi.
authors: Niina
authors: N
authors: Lietzen
authors: Steno Diabetes Center A/S, Niels Steensens Vej 2, 2820 Gentofte, Denmark. Electronic address: imat@steno.dk.
authors: Ismo
authors: I
authors: Mattila
authors: Eastern Finland Laboratory Centre, Puijonlaaksontie 2, 70210 Kuopio, Finland. Electronic address: anu.olkku@islab.fi.
authors: Anu
authors: A
authors: Olkku
authors: Steno Diabetes Center A/S, Niels Steensens Vej 2, 2820 Gentofte, Denmark. Electronic address: tuulia.hyotylainen@utu.fi.
authors: Tuulia
authors: T
authors: Hyötyläinen
authors: Steno Diabetes Center A/S, Niels Steensens Vej 2, 2820 Gentofte, Denmark. Electronic address: matej.oresic@utu.fi.
authors: Matej
authors: M
authors: Orešič
authors: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: olli.simell@utu.fi.
authors: Olli
authors: O
authors: Simell
authors: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland. Electronic address: harri.niinikoski@tyks.fi.
authors: Harri
authors: H
authors: Niinikoski
authors: Department of Pediatrics, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, PL 52, 20521 Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. Electronic address: juha.mykkanen@utu.fi.
authors: Juha
authors: J
authors: Mykkänen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood*; D000596:Amino Acids / Q000097:blood*; D000601:Amino Acids, Essential / Q000097:blood; D050260:Carbohydrate Metabolism; D002648:Child; D018450:Disease Progression; D004734:Energy Metabolism; D005260:Female; D005387:Finland; D005919:Glomerular Filtration Rate; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood*; D008239:Lysine / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009573:Nitrites / Q000097:blood; D010713:Phosphatidylcholines / Q000097:blood; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D000596:Amino Acids; D000601:Amino Acids, Essential; D008055:Lipids; D009573:Nitrites; D010713:Phosphatidylcholines; D014280:Triglycerides; D008239:Lysine
keywords: Chronic kidney disease; Combined hyperlipidemia; Lipidomics; Lysinuric protein intolerance; Metabolomics