Indole-3-propionic acid promotes hepatic stellate cells inactivation
Abstract Background & aims We have previously reported that the serum levels of gut-derived tryptophan metabolite indole-3-propionic acid (IPA) are lower in individuals with liver fibrosis. Now, we explored the transcriptome and DNA methylome associated with serum IPA levels in human liver from...
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BMC
2025-03-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06266-z |
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| author | Mariana Ilha Ratika Sehgal Johanna Matilainen Kirsi Rilla Dorota Kaminska Shrey Gandhi Ville Männistö Charlotte Ling Stefano Romeo Päivi Pajukanta Eija Pirinen Kirsi A. Virtanen Kirsi H. Pietiläinen Maija Vaittinen Jussi Pihlajamäki |
| author_facet | Mariana Ilha Ratika Sehgal Johanna Matilainen Kirsi Rilla Dorota Kaminska Shrey Gandhi Ville Männistö Charlotte Ling Stefano Romeo Päivi Pajukanta Eija Pirinen Kirsi A. Virtanen Kirsi H. Pietiläinen Maija Vaittinen Jussi Pihlajamäki |
| author_sort | Mariana Ilha |
| collection | DOAJ |
| description | Abstract Background & aims We have previously reported that the serum levels of gut-derived tryptophan metabolite indole-3-propionic acid (IPA) are lower in individuals with liver fibrosis. Now, we explored the transcriptome and DNA methylome associated with serum IPA levels in human liver from obese individuals together with IPA effects on shifting the hepatic stellate cell (HSC) phenotype to inactivation in vitro. Methods A total of 116 obese individuals without type 2 diabetes (T2D) (age 46.8 ± 9.3 years; BMI: 42.7 ± 5.0 kg/m2) from the Kuopio OBesity Surgery (KOBS) study undergoing bariatric surgery were included. Circulating IPA levels were measured using LC–MS, liver transcriptomics with total RNA-sequencing and DNA methylation with Infinium HumanMethylation450 BeadChip. Human hepatic stellate cells (LX-2) where used for in vitro experiments. Results Serum IPA levels were associated with the expression of liver genes enriched for apoptosis, mitophagy and longevity pathways in the liver. AKT serine/threonine kinase 1 (AKT1) was the shared and topmost interactive gene from the liver transcript and DNA methylation profile. IPA treatment induced apoptosis, reduced mitochondrial respiration as well as modified cell morphology, and mitochondrial dynamics by modulating the expression of genes known to regulate fibrosis, apoptosis, and survival in LX-2 cells. Conclusion In conclusion, these data support that IPA has a plausible therapeutic effect and may induce apoptosis and the HSC phenotype towards the inactivation state, extending the possibilities to suppress hepatic fibrogenesis by interfering with HSC activation and mitochondrial metabolism. Graphical Abstract |
| format | Article |
| id | doaj-art-cb871666bb804231b4d74762b1439ee2 |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-cb871666bb804231b4d74762b1439ee22025-08-20T02:15:07ZengBMCJournal of Translational Medicine1479-58762025-03-0123111810.1186/s12967-025-06266-zIndole-3-propionic acid promotes hepatic stellate cells inactivationMariana Ilha0Ratika Sehgal1Johanna Matilainen2Kirsi Rilla3Dorota Kaminska4Shrey Gandhi5Ville Männistö6Charlotte Ling7Stefano Romeo8Päivi Pajukanta9Eija Pirinen10Kirsi A. Virtanen11Kirsi H. Pietiläinen12Maija Vaittinen13Jussi Pihlajamäki14Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern FinlandInstitute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern FinlandInstitute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern FinlandInstitute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern FinlandInstitute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern FinlandInstitute of Immunology, University of MünsterDepartments of Medicine, University of Eastern Finland and Kuopio University HospitalEpigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Scania University HospitalDepartment of Molecular and Clinical Medicine, University of GothenburgDepartment of Human Genetics, David Geffen School of Medicine at University of California Los Angeles (UCLA)Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiTurku PET Centre, University of TurkuObesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiInstitute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern FinlandInstitute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern FinlandAbstract Background & aims We have previously reported that the serum levels of gut-derived tryptophan metabolite indole-3-propionic acid (IPA) are lower in individuals with liver fibrosis. Now, we explored the transcriptome and DNA methylome associated with serum IPA levels in human liver from obese individuals together with IPA effects on shifting the hepatic stellate cell (HSC) phenotype to inactivation in vitro. Methods A total of 116 obese individuals without type 2 diabetes (T2D) (age 46.8 ± 9.3 years; BMI: 42.7 ± 5.0 kg/m2) from the Kuopio OBesity Surgery (KOBS) study undergoing bariatric surgery were included. Circulating IPA levels were measured using LC–MS, liver transcriptomics with total RNA-sequencing and DNA methylation with Infinium HumanMethylation450 BeadChip. Human hepatic stellate cells (LX-2) where used for in vitro experiments. Results Serum IPA levels were associated with the expression of liver genes enriched for apoptosis, mitophagy and longevity pathways in the liver. AKT serine/threonine kinase 1 (AKT1) was the shared and topmost interactive gene from the liver transcript and DNA methylation profile. IPA treatment induced apoptosis, reduced mitochondrial respiration as well as modified cell morphology, and mitochondrial dynamics by modulating the expression of genes known to regulate fibrosis, apoptosis, and survival in LX-2 cells. Conclusion In conclusion, these data support that IPA has a plausible therapeutic effect and may induce apoptosis and the HSC phenotype towards the inactivation state, extending the possibilities to suppress hepatic fibrogenesis by interfering with HSC activation and mitochondrial metabolism. Graphical Abstracthttps://doi.org/10.1186/s12967-025-06266-zIndole-3-propionic acidLiver fibrosisHepatic stellate cellsApoptosisMitochondrial metabolismEpigenetics |
| spellingShingle | Mariana Ilha Ratika Sehgal Johanna Matilainen Kirsi Rilla Dorota Kaminska Shrey Gandhi Ville Männistö Charlotte Ling Stefano Romeo Päivi Pajukanta Eija Pirinen Kirsi A. Virtanen Kirsi H. Pietiläinen Maija Vaittinen Jussi Pihlajamäki Indole-3-propionic acid promotes hepatic stellate cells inactivation Journal of Translational Medicine Indole-3-propionic acid Liver fibrosis Hepatic stellate cells Apoptosis Mitochondrial metabolism Epigenetics |
| title | Indole-3-propionic acid promotes hepatic stellate cells inactivation |
| title_full | Indole-3-propionic acid promotes hepatic stellate cells inactivation |
| title_fullStr | Indole-3-propionic acid promotes hepatic stellate cells inactivation |
| title_full_unstemmed | Indole-3-propionic acid promotes hepatic stellate cells inactivation |
| title_short | Indole-3-propionic acid promotes hepatic stellate cells inactivation |
| title_sort | indole 3 propionic acid promotes hepatic stellate cells inactivation |
| topic | Indole-3-propionic acid Liver fibrosis Hepatic stellate cells Apoptosis Mitochondrial metabolism Epigenetics |
| url | https://doi.org/10.1186/s12967-025-06266-z |
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