Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI)

Johanna Kurko (Corresponding Author), Maaria Tringham, Laura Tanner, Kirsti Näntö-Salonen, Mari Vähä-Mäkilä, Heli Nygren, Päivi Pöhö, Niina Lietzen, Ismo Mattila, Anu Olkku, Tuulia Hyötyläinen, Matej Oresic, Olli Simell, Harri Niinikoski, Juha Mykkänen

Research output: Contribution to journalArticleScientificpeer-review

5 Citations (Scopus)

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.
Original languageEnglish
Pages (from-to)1361-1375
JournalMetabolism: clinical and experimental
Volume65
Issue number9
DOIs
Publication statusPublished - 2016
MoE publication typeA1 Journal article-refereed

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Chronic Renal Insufficiency
Lipids
Amino Acids
Triglycerides
Hyperammonemia
Failure to Thrive
Proximal Kidney Tubule
Metabolome
Inositol
Nitrites
Lysinuric Protein Intolerance
Hyperlipidemias
Phosphatidylcholines
Lipid Metabolism
Malnutrition
Small Intestine
Intestines
Oxidative Stress
Fibrosis
Epithelial Cells

Keywords

  • chronic kidney disease
  • combined hyperlipidemia
  • lipidomics
  • lysinuric protein intolerance
  • metabolomics

Cite this

Kurko, Johanna ; Tringham, Maaria ; Tanner, Laura ; Näntö-Salonen, Kirsti ; Vähä-Mäkilä, Mari ; Nygren, Heli ; Pöhö, Päivi ; Lietzen, Niina ; Mattila, Ismo ; Olkku, Anu ; Hyötyläinen, Tuulia ; Oresic, Matej ; Simell, Olli ; Niinikoski, Harri ; Mykkänen, Juha. / Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI). In: Metabolism: clinical and experimental. 2016 ; Vol. 65, No. 9. pp. 1361-1375.
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title = "Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI)",
abstract = "Background 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. Methods 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. Results 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. Conclusions 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.",
keywords = "chronic kidney disease, combined hyperlipidemia, lipidomics, lysinuric protein intolerance, metabolomics",
author = "Johanna Kurko and Maaria Tringham and Laura Tanner and Kirsti N{\"a}nt{\"o}-Salonen and Mari V{\"a}h{\"a}-M{\"a}kil{\"a} and Heli Nygren and P{\"a}ivi P{\"o}h{\"o} and Niina Lietzen and Ismo Mattila and Anu Olkku and Tuulia Hy{\"o}tyl{\"a}inen and Matej Oresic and Olli Simell and Harri Niinikoski and Juha Mykk{\"a}nen",
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Kurko, J, Tringham, M, Tanner, L, Näntö-Salonen, K, Vähä-Mäkilä, M, Nygren, H, Pöhö, P, Lietzen, N, Mattila, I, Olkku, A, Hyötyläinen, T, Oresic, M, Simell, O, Niinikoski, H & Mykkänen, J 2016, 'Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI)', Metabolism: clinical and experimental, vol. 65, no. 9, pp. 1361-1375. https://doi.org/10.1016/j.metabol.2016.05.012

Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI). / Kurko, Johanna (Corresponding Author); Tringham, Maaria; Tanner, Laura; Näntö-Salonen, Kirsti; Vähä-Mäkilä, Mari; Nygren, Heli; Pöhö, Päivi; Lietzen, Niina; Mattila, Ismo; Olkku, Anu; Hyötyläinen, Tuulia; Oresic, Matej; Simell, Olli; Niinikoski, Harri; Mykkänen, Juha.

In: Metabolism: clinical and experimental, Vol. 65, No. 9, 2016, p. 1361-1375.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI)

AU - Kurko, Johanna

AU - Tringham, Maaria

AU - Tanner, Laura

AU - Näntö-Salonen, Kirsti

AU - Vähä-Mäkilä, Mari

AU - Nygren, Heli

AU - Pöhö, Päivi

AU - Lietzen, Niina

AU - Mattila, Ismo

AU - Olkku, Anu

AU - Hyötyläinen, Tuulia

AU - Oresic, Matej

AU - Simell, Olli

AU - Niinikoski, Harri

AU - Mykkänen, Juha

PY - 2016

Y1 - 2016

N2 - Background 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. Methods 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. Results 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. Conclusions 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.

AB - Background 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. Methods 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. Results 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. Conclusions 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.

KW - chronic kidney disease

KW - combined hyperlipidemia

KW - lipidomics

KW - lysinuric protein intolerance

KW - metabolomics

UR - http://www.metabolismjournal.com/issue/S0026-0495(16)X0006-6

U2 - 10.1016/j.metabol.2016.05.012

DO - 10.1016/j.metabol.2016.05.012

M3 - Article

VL - 65

SP - 1361

EP - 1375

JO - Metabolism: clinical and experimental

JF - Metabolism: clinical and experimental

SN - 0026-0495

IS - 9

ER -