Metabolic Analysis of Nucleosides/Bases in the Urine and Serum of Patients with Alcohol-Associated Liver Disease

He, Liqing; Vatsalya, Vatsalya; Ma, Xipeng; Klinge, Carolyn M.; Cave, Matthew C.; Feng, Wenke; McClain, Craig J.; Zhang, Xiang

doi:10.3390/metabo12121187

Cited by 6 publications

(3 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The aim of the current study was to generate mechanistic hypotheses by RNA-Seq and to subsequently test these hypotheses. Excessive alcohol consumption has been shown to impact a wealth of molecules such as nucleic acids, 37 , 38 proteins, 21 , 37 cofactors, 37 and various micronutrients. 39 , 40 Thus, it was no major surprise to find that some differences in these molecules that were identified following EtOH exposure, such as Zn, were worsened after PCB126 exposure.…”

Section: Discussionmentioning

confidence: 99%

Multiomics Analysis of PCB126’s Effect on a Mouse Chronic-Binge Alcohol Feeding Model

Gripshover,

Wahlang,

Head

et al. 2024

Environ Health Perspect

Self Cite

View full text Add to dashboard Cite

Background: Environmental pollutants, including polychlorinated biphenyls (PCBs) have been implicated in the pathogenesis of liver disease. Our group recently demonstrated that PCB126 promoted steatosis, hepatomegaly, and modulated intermediary metabolism in a rodent model of alcohol-associated liver disease (ALD). Objective: To better understand how PCB126 promoted ALD in our previous model, the current study adopts multiple omics approaches to elucidate potential mechanistic hypotheses. Methods: Briefly, male C57BL/6J mice were exposed to polychlorinated biphenyl (PCB) 126 or corn oil vehicle prior to ethanol (EtOH) or control diet feeding in the chronic-binge alcohol feeding model. Liver tissues were collected and prepared for mRNA sequencing, phosphoproteomics, and inductively coupled plasma mass spectrometry for metals quantification. Results: Principal component analysis showed that PCB126 uniquely modified the transcriptome in EtOH-fed mice. EtOH feeding alone resulted in differentially expressed genes (DEGs), and PCB126 exposure resulted in more DEGs in the EtOH-fed group (907 DEGs) in comparison with the pair-fed group (503 DEGs). Top 20 significant gene ontology (GO) biological processes included “peptidyl tyrosine modifications,” whereas top 25 significantly decreasing GO molecular functions included “metal/ion/zinc binding.” Quantitative, label-free phosphoproteomics and western blot analysis revealed no major significant PCB126 effects on total phosphorylated tyrosine residues in EtOH-fed mice. Quantified hepatic essential metal levels were primarily significantly lower in EtOH-fed mice. PCB126-exposed mice had significantly lower magnesium, cobalt, and zinc levels in EtOH-fed mice. Discussion: Previous work has demonstrated that PCB126 is a modifying factor in metabolic dysfunction-associated steatotic liver disease (MASLD), and our current work suggests that pollutants also modify ALD. PCB126 may, in part, be contributing to the malnutrition aspect of ALD, where metal deficiency is known to contribute and worsen prognosis. https://doi.org/10.1289/EHP14132

show abstract

Section: Discussionmentioning

confidence: 99%

Multiomics Analysis of PCB126’s Effect on a Mouse Chronic-Binge Alcohol Feeding Model

Gripshover,

Wahlang,

Head

et al. 2024

Environ Health Perspect

Self Cite

View full text Add to dashboard Cite

show abstract

“…The clinical study was approved by the University of Louisville Institutional Review Board. Information on general patient definitions and recruitment is detailed in other publications (He et al, 2022; Xu et al, 2023). All study participants provided informed consent before the study, including appropriate authorization for data, sample collection and usage of urine samples for this investigation.…”

Section: Methodsmentioning

confidence: 99%

Altered urinary tryptophan metabolites in alcohol‐associated liver disease

Vatsalya

et al. 2023

Alcohol: Clinical and Experimental Research

Self Cite

View full text Add to dashboard Cite

BackgroundAlcohol‐associated liver disease (ALD) leads to millions of deaths worldwide annually. A few potential biomarkers of ALD have been discovered through metabolomic or proteomic analysis. Tryptophan (Trp), one of nine essential amino acids, has been extensively studied and shown to play significant roles in many mammalian physiological processes. However, Trp metabolism changes in ALD are not yet fully understood. Whereas urine is an abundant and non‐invasive source for disease biomarker discovery the current study investigated whether the abundance of Trp metabolites in the urine of ALD patients differs from that of healthy subjects. We also examined whether, if present in ALD, changes in urinary Trp metabolites can serve as markers for differentiating between mild/moderate and severe ALD.MethodsWe quantified the concentration of Trp and its metabolites in urine samples of healthy controls (n = 18), patients with mild or moderate alcohol‐related liver injury (non‐severe ALD; n = 21), and patients with severe alcohol‐associated hepatitis (severe AH; n = 25) using both untargeted and targeted metabolomics.ResultsEighteen Trp metabolites were identified and quantified from the untargeted metabolomics data. We developed a targeted metabolomics method to quantify the Trp and its metabolites and quantified 17 metabolites from the human urine samples. The data acquired in the untargeted and targeted platforms agreed and showed that the Trp concentration is not affected by the severity of ALD. However, the abundance of 10 Trp metabolites was correlated with the model for end‐stage liver disease (MELD) score, with the abundance of nine metabolites significantly different between the healthy control and ALD patient groups.ConclusionWe found that Trp metabolism differs between ALD patients and healthy controls even though the concentration of Trp was not affected. Two Trp metabolites, quinolinic acid and indoxyl sulfate, correlate highly with the severity of ALD.

show abstract

“…We recently published on modified nucleotides and bases circulating in the blood or urine of human subjects with alcohol-associated liver disease (ALD). While numerous modified bases were significantly altered, m6A was unchanged [ 173 ]. The abundance of modified nucleobase and ribonucleoside, 7,9-dimethylguanine in urine and 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in serum were strongly associated with the severity of the ALD.…”

Section: M6a In Nafldmentioning

confidence: 99%

Changes in m6A in Steatotic Liver Disease

Petri,

Cave,

Klinge

2023

Genes

Self Cite

View full text Add to dashboard Cite

Fatty liver disease is one of the major causes of morbidity and mortality worldwide. Fatty liver includes non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), now replaced by a consensus group as metabolic dysfunction-associated steatotic liver disease (MASLD). While excess nutrition and obesity are major contributors to fatty liver, the underlying mechanisms remain largely unknown and therapeutic interventions are limited. Reversible chemical modifications in RNA are newly recognized critical regulators controlling post-transcriptional gene expression. Among these modifications, N6-methyladenosine (m6A) is the most abundant and regulates transcript abundance in fatty liver disease. Modulation of m6A by readers, writers, and erasers (RWE) impacts mRNA processing, translation, nuclear export, localization, and degradation. While many studies focus on m6A RWE expression in human liver pathologies, limitations of technology and bioinformatic methods to detect m6A present challenges in understanding the epitranscriptomic mechanisms driving fatty liver disease progression. In this review, we summarize the RWE of m6A and current methods of detecting m6A in specific genes associated with fatty liver disease.

show abstract

Metabolic Analysis of Nucleosides/Bases in the Urine and Serum of Patients with Alcohol-Associated Liver Disease

Cited by 6 publications

References 35 publications

Multiomics Analysis of PCB126’s Effect on a Mouse Chronic-Binge Alcohol Feeding Model

Multiomics Analysis of PCB126’s Effect on a Mouse Chronic-Binge Alcohol Feeding Model

Altered urinary tryptophan metabolites in alcohol‐associated liver disease

Changes in m6A in Steatotic Liver Disease

Contact Info

Product

Resources

About