TAT as a new marker and its use for noninvasive chemical biopsy in NASH diagnosis
Abstract Background Early diagnosis of Nonalcoholic steatohepatitis (NASH) is crucial to prevent its progression to hepatocellular carcinoma, but its gold standard diagnosis still requires invasive biopsy. Here, a new marker-based noninvasive chemical biopsy approach is introduced that uses urine-se...
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BMC
2024-11-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-024-00992-8 |
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| author | Sihyang Jo Jin-Mo Kim Minshu Li Han Sun Kim Yong Jin An Sunghyouk Park |
| author_facet | Sihyang Jo Jin-Mo Kim Minshu Li Han Sun Kim Yong Jin An Sunghyouk Park |
| author_sort | Sihyang Jo |
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| description | Abstract Background Early diagnosis of Nonalcoholic steatohepatitis (NASH) is crucial to prevent its progression to hepatocellular carcinoma, but its gold standard diagnosis still requires invasive biopsy. Here, a new marker-based noninvasive chemical biopsy approach is introduced that uses urine-secreted tyrosine metabolites. Methods We first identified NASH-specific decrease in TAT expression, the first enzyme in the tyrosine degradation pathway (TDP), by employing exometabolome-transcriptome correlations, single-cell RNA -seq, and tissue staining on human NASH patient samples. A selective extrahepatic monitoring of the TAT activity was established by the chemical biopsy exploiting the enzyme’s metabolic conversion of D2-tyrosine into D2-4HPP. The approach was applied to a NASH mouse model using the methionine-choline deficient diet, where urine D2-4HPP level was measured with a specific LC-MS detection, following oral administration of D2-tyrosine. Results The noninvasive urine chemical biopsy approach could effectively differentiate NASH from normal mice (normal = 14, NASH = 15, p = 0.0054), correlated with the NASH pathology and TAT level decrease observed with immunostaining on the liver tissue. In addition, we showed that the diagnostic differentiation could be enhanced by measuring the downstream metabolites of TDP. The specificity of the TAT and the related TDP enzymes in NASH were also addressed in other settings employing high fat high fructose mouse NASH model and human obesity vs. NASH cohort. Conclusions Overall, we propose TAT and TDP as pathology-relevant markers for NASH and present the urine chemical biopsy as a noninvasive modality to evaluate the NASH-specific changes in urine that may help the NASH diagnosis. |
| format | Article |
| id | doaj-art-f842ccdb310f49cdba1c62fe7c5bcfe6 |
| institution | Kabale University |
| issn | 1528-3658 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
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| series | Molecular Medicine |
| spelling | doaj-art-f842ccdb310f49cdba1c62fe7c5bcfe62024-12-01T12:31:04ZengBMCMolecular Medicine1528-36582024-11-0130111210.1186/s10020-024-00992-8TAT as a new marker and its use for noninvasive chemical biopsy in NASH diagnosisSihyang Jo0Jin-Mo Kim1Minshu Li2Han Sun Kim3Yong Jin An4Sunghyouk Park5Natural Products Research Institute, College of Pharmacy, Seoul National UniversityNatural Products Research Institute, College of Pharmacy, Seoul National UniversityNatural Products Research Institute, College of Pharmacy, Seoul National UniversityNatural Products Research Institute, College of Pharmacy, Seoul National UniversityNatural Products Research Institute, College of Pharmacy, Seoul National UniversityNatural Products Research Institute, College of Pharmacy, Seoul National UniversityAbstract Background Early diagnosis of Nonalcoholic steatohepatitis (NASH) is crucial to prevent its progression to hepatocellular carcinoma, but its gold standard diagnosis still requires invasive biopsy. Here, a new marker-based noninvasive chemical biopsy approach is introduced that uses urine-secreted tyrosine metabolites. Methods We first identified NASH-specific decrease in TAT expression, the first enzyme in the tyrosine degradation pathway (TDP), by employing exometabolome-transcriptome correlations, single-cell RNA -seq, and tissue staining on human NASH patient samples. A selective extrahepatic monitoring of the TAT activity was established by the chemical biopsy exploiting the enzyme’s metabolic conversion of D2-tyrosine into D2-4HPP. The approach was applied to a NASH mouse model using the methionine-choline deficient diet, where urine D2-4HPP level was measured with a specific LC-MS detection, following oral administration of D2-tyrosine. Results The noninvasive urine chemical biopsy approach could effectively differentiate NASH from normal mice (normal = 14, NASH = 15, p = 0.0054), correlated with the NASH pathology and TAT level decrease observed with immunostaining on the liver tissue. In addition, we showed that the diagnostic differentiation could be enhanced by measuring the downstream metabolites of TDP. The specificity of the TAT and the related TDP enzymes in NASH were also addressed in other settings employing high fat high fructose mouse NASH model and human obesity vs. NASH cohort. Conclusions Overall, we propose TAT and TDP as pathology-relevant markers for NASH and present the urine chemical biopsy as a noninvasive modality to evaluate the NASH-specific changes in urine that may help the NASH diagnosis.https://doi.org/10.1186/s10020-024-00992-8Nonalcoholic steatohepatitisBiomarkerNoninvasiveChemical biopsyLiquid biopsyStable isotopes |
| spellingShingle | Sihyang Jo Jin-Mo Kim Minshu Li Han Sun Kim Yong Jin An Sunghyouk Park TAT as a new marker and its use for noninvasive chemical biopsy in NASH diagnosis Molecular Medicine Nonalcoholic steatohepatitis Biomarker Noninvasive Chemical biopsy Liquid biopsy Stable isotopes |
| title | TAT as a new marker and its use for noninvasive chemical biopsy in NASH diagnosis |
| title_full | TAT as a new marker and its use for noninvasive chemical biopsy in NASH diagnosis |
| title_fullStr | TAT as a new marker and its use for noninvasive chemical biopsy in NASH diagnosis |
| title_full_unstemmed | TAT as a new marker and its use for noninvasive chemical biopsy in NASH diagnosis |
| title_short | TAT as a new marker and its use for noninvasive chemical biopsy in NASH diagnosis |
| title_sort | tat as a new marker and its use for noninvasive chemical biopsy in nash diagnosis |
| topic | Nonalcoholic steatohepatitis Biomarker Noninvasive Chemical biopsy Liquid biopsy Stable isotopes |
| url | https://doi.org/10.1186/s10020-024-00992-8 |
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