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Serum aromatic and branched-chain amino acids associated with NASH demonstrate divergent associations with serum lipids

de Mello, Vanessa D. ; Sehgal, Ratika ; Männistö, Ville ; Klåvus, Anton ; Nilsson, Emma A LU orcid ; Perfilyev, Alexander LU orcid ; Kaminska, Dorota ; Miao, Zong ; Pajukanta, Päivi and Ling, Charlotte LU orcid , et al. (2021) In Liver International 41(4). p.754-763
Abstract

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has been associated with multiple metabolic abnormalities. By applying a non-targeted metabolomics approach, we aimed at investigating whether serum metabolite profile that associates with NAFLD would differ in its association with NAFLD-related metabolic risk factors. Methods & Results: A total of 233 subjects (mean ± SD: 48.3 ± 9.3 years old; BMI: 43.1 ± 5.4 kg/m2; 64 male) undergoing bariatric surgery were studied. Of these participants, 164 with liver histology could be classified as normal liver (n = 79), simple steatosis (SS, n = 40) or non-alcoholic steatohepatitis (NASH, n = 45). Among the identified fasting serum metabolites with higher levels in... (More)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has been associated with multiple metabolic abnormalities. By applying a non-targeted metabolomics approach, we aimed at investigating whether serum metabolite profile that associates with NAFLD would differ in its association with NAFLD-related metabolic risk factors. Methods & Results: A total of 233 subjects (mean ± SD: 48.3 ± 9.3 years old; BMI: 43.1 ± 5.4 kg/m2; 64 male) undergoing bariatric surgery were studied. Of these participants, 164 with liver histology could be classified as normal liver (n = 79), simple steatosis (SS, n = 40) or non-alcoholic steatohepatitis (NASH, n = 45). Among the identified fasting serum metabolites with higher levels in those with NASH when compared to those with normal phenotype were the aromatic amino acids (AAAs: tryptophan, tyrosine and phenylalanine), the branched-chain amino acids (BCAAs: leucine and isoleucine), a phosphatidylcholine (PC(16:0/16:1)) and uridine (all FDRp < 0.05). Only tryptophan was significantly higher in those with NASH compared to those with SS (FDRp < 0.05). Only the AAAs tryptophan and tyrosine correlated positively with serum total and LDL cholesterol (FDRp < 0.1), and accordingly, with liver LDLR at mRNA expression level. In addition, tryptophan was the single AA associated with liver DNA methylation of CpG sites known to be differentially methylated in those with NASH. Conclusions: We found that serum levels of the NASH-related AAAs and BCAAs demonstrate divergent associations with serum lipids. The specific correlation of tryptophan with LDL-c may result from the molecular events affecting LDLR mRNA expression and NASH-associated methylation of genes in the liver.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aromatic amino acids, DNA methylation, epigenetics, LDL cholesterol, NAFLD, NASH, non-targeted metabolomics, tryptophan
in
Liver International
volume
41
issue
4
pages
754 - 763
publisher
Wiley-Blackwell
external identifiers
  • pmid:33219609
  • scopus:85097102859
ISSN
1478-3223
DOI
10.1111/liv.14743
language
English
LU publication?
yes
id
eebf59c1-4526-4298-81e3-e07e1379f749
date added to LUP
2021-01-11 16:45:20
date last changed
2025-01-11 02:13:07
@article{eebf59c1-4526-4298-81e3-e07e1379f749,
  abstract     = {{<p>Background &amp; Aims: Non-alcoholic fatty liver disease (NAFLD) has been associated with multiple metabolic abnormalities. By applying a non-targeted metabolomics approach, we aimed at investigating whether serum metabolite profile that associates with NAFLD would differ in its association with NAFLD-related metabolic risk factors. Methods &amp; Results: A total of 233 subjects (mean ± SD: 48.3 ± 9.3 years old; BMI: 43.1 ± 5.4 kg/m<sup>2</sup>; 64 male) undergoing bariatric surgery were studied. Of these participants, 164 with liver histology could be classified as normal liver (n = 79), simple steatosis (SS, n = 40) or non-alcoholic steatohepatitis (NASH, n = 45). Among the identified fasting serum metabolites with higher levels in those with NASH when compared to those with normal phenotype were the aromatic amino acids (AAAs: tryptophan, tyrosine and phenylalanine), the branched-chain amino acids (BCAAs: leucine and isoleucine), a phosphatidylcholine (PC(16:0/16:1)) and uridine (all FDRp &lt; 0.05). Only tryptophan was significantly higher in those with NASH compared to those with SS (FDRp &lt; 0.05). Only the AAAs tryptophan and tyrosine correlated positively with serum total and LDL cholesterol (FDRp &lt; 0.1), and accordingly, with liver LDLR at mRNA expression level. In addition, tryptophan was the single AA associated with liver DNA methylation of CpG sites known to be differentially methylated in those with NASH. Conclusions: We found that serum levels of the NASH-related AAAs and BCAAs demonstrate divergent associations with serum lipids. The specific correlation of tryptophan with LDL-c may result from the molecular events affecting LDLR mRNA expression and NASH-associated methylation of genes in the liver.</p>}},
  author       = {{de Mello, Vanessa D. and Sehgal, Ratika and Männistö, Ville and Klåvus, Anton and Nilsson, Emma A and Perfilyev, Alexander and Kaminska, Dorota and Miao, Zong and Pajukanta, Päivi and Ling, Charlotte and Hanhineva, Kati and Pihlajamäki, Jussi}},
  issn         = {{1478-3223}},
  keywords     = {{aromatic amino acids; DNA methylation; epigenetics; LDL cholesterol; NAFLD; NASH; non-targeted metabolomics; tryptophan}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{754--763}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Liver International}},
  title        = {{Serum aromatic and branched-chain amino acids associated with NASH demonstrate divergent associations with serum lipids}},
  url          = {{http://dx.doi.org/10.1111/liv.14743}},
  doi          = {{10.1111/liv.14743}},
  volume       = {{41}},
  year         = {{2021}},
}