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Serum Bile Acid, Vitamin E, and Serotonin Metabolites Are Associated With Future Liver-Related Events in Nonalcoholic Fatty Liver Disease.

ABSTRACT: Identifying patients at higher risk for poor outcomes from nonalcoholic fatty liver disease (NAFLD) remains challenging. Metabolomics, the comprehensive measurement of small molecules in biological samples, has the potential to reveal novel noninvasive biomarkers. The aim of this study was to determine if serum metabolite profiles in patients with NAFLD associate with future liver-related events. We performed a retrospective single-center cohort study of 187 participants with biopsy-proven NAFLD. Metabolomic analysis was performed on serum using ultrahigh performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. We identified liver-related events (variceal bleeding, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatocellular carcinoma, hepatopulmonary or hepatorenal syndrome) by manual chart review between index biopsy (2007-2013) and April 1, 2018. Generalized linear models and Cox proportional hazards models were used to test the association of metabolites with liver-related events and time to first liver-related event, controlling for covariates and fibrosis stage. Over a mean ± SD follow-up of 6.9 ± 3.2 years, 11 participants experienced 22 liver-related events. Generalized linear models revealed 53 metabolites significantly associated with liver-related events (P < 0.05). In Cox proportional hazards modeling, 69 metabolites were significantly associated with time to future liver-related events (P < 0.05), seven of which met the false discovery rate threshold of 0.10: vitamin E metabolites gamma-carboxyethyl-hydroxychroman (gamma-CEHC) and gamma-CEHC glucuronide; primary bile acid metabolite taurochenodeoxycholate; serotonin metabolite 5-hydroxyindoleacetate; and lipid metabolites (i) 2-hydroxyglutarate, (ii) 3beta,17beta-diol disulfate 1, and (iii) eicosenoyl sphingomyelin. Conclusion: Metabolites of a primary bile acid, vitamin E, and serotonin were associated with future liver-related events. Our results suggest metabolite pathways may be useful for predicting which patients with NAFLD are at higher risk for hepatic decompensation.

SUBMITTER: Wegermann K

PROVIDER: S-EPMC8034573 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Changes in bile acids (BAs) are increasingly recognized as potential targets for non-alcoholic steatohepatitis (NASH). Kaempferol has been proved to be anti-inflammatory and reduce the disorder of lipid metabolism. In order to analyze the BA profile in NASH mice and determine the predictive biomarkers of kaempferol treatment, serum-targeted metabolomics and liver tissue RNA sequencing (RNA-seq) were carried out. Design: Six normal control mice (NC group), eight HFD-fed mice (HFD group), and eight kaempferol-treated HFD-fed mice (HFD + KP group) were included in the present study. Ultra-performance liquid chromatography coupled to a tandem mass spectrometry system (UPLC-MS/MS) was used to quantify serum and liver BAs, and RNA-seq was used to quantify liver differentially expressed genes related to BA metabolism. Results: The serum levels of CA, βMCA, UDCA, and 12-DHCA, as well as ωMCA in both the serum and liver, were significantly decreased in the HFD group compared with those in the NC group, and kaempferol can increase the serum levels of βMCA, UDCA, and ωMCA and the liver level of 12-DHCA. The serum levels of TDCA, THDCA, TUDCA, TDCA/CA, and TDCA/DCA were significantly increased in the HFD group compared with those of the NC group, and kaempferol can decrease them. Furthermore, NASH mice had a higher liver level of total CA%, total CDCA%, primary BAs/secondary BAs, 12α-OH BAs/non-12α-OH Bas, and conjugated BAs/unconjugated BAs, and all decreased after kaempferol treatment. According to the RNA-seq results, we found that compared with the NC group, the mRNA expression of cholesterol-7α-hydroxylase (CYP7A1) in the HFD group was significantly increased, and the mRNA expression of sterol 12α-hydroxylase (CYP8B1) and multidrug resistance-related protein 3 (MRP3) was significantly decreased, while kaempferol significantly promoted the mRNA expression of mitochondrial sterol 27-hydroxylase (CYP27A1) and Na+ -taurocholate cotransporting polypeptide (NTCP). Conclusion: βMCA, CA, UDCA, 12-DHCA, ωMCA, CDCA, TωMCA, TDCA, THDCA, TCDCA, and TUDCA in the serum, as well as 6,7-diketoLCA, 12-DHCA, and ωMCA in the liver, may be potential biomarkers for kaempferol to improve NASH. HFD-induced NASH may be associated with the increase of CYP7A1 and the decrease of CYP8B1, leading to increased BA synthesis, and the decrease of MRP3 leading to decreased BA synthesis, and kaempferol may alleviate NASH by increasing CYP27A1 and NTCP to enhance BA transport.

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Serum Bile Acid, Vitamin E, and Serotonin Metabolites Are Associated With Future Liver-Related Events in Nonalcoholic Fatty Liver Disease.

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