期刊
LIVER INTERNATIONAL
卷 41, 期 4, 页码 754-763出版社
WILEY
DOI: 10.1111/liv.14743
关键词
aromatic amino acids; DNA methylation; epigenetics; LDL cholesterol; NAFLD; NASH; non‐ targeted metabolomics; tryptophan
资金
- Finnish Diabetes Research Foundation
- Kuopio University Hospital Project [2005-2019]
- Academy of Finland [138006, 316458]
- Finnish Cultural Foundation
- University of Eastern Finland
- Horizon 2020 Framework Programme of the European Union [740264]
- National Institutes of Health (NIH) [HL-095056, HL-28481, U01 DK105561]
- Academy of Finland (AKA) [316458, 316458] Funding Source: Academy of Finland (AKA)
This study investigated the serum metabolite profile in relation to NAFLD-associated metabolic risk factors using a non-targeted metabolomics approach. The results showed that the AAAs and BCAAs related to NASH demonstrate divergent associations with serum lipids. Specifically, tryptophan correlated with LDL-c, potentially due to molecular events affecting LDLR mRNA expression and methylation of genes associated with NASH.
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/m(2); 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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