Indole-3-propionic acid promotes hepatic stellate cells inactivation
Ilha, Mariana; Sehgal, Ratika; Matilainen, Johanna; Rilla, Kirsi; Kaminska, Dorota; Gandhi, Shrey; Männistö, Ville; Ling, Charlotte; Romeo, Stefano; Pajukanta, Päivi; Pirinen, Eija; Virtanen, Kirsi A; Pietiläinen, Kirsi H; Vaittinen, Maija; Pihlajamäki, Jussi (2025-03-01)
Biomed central
01.03.2025
Ilha, M., Sehgal, R., Matilainen, J. et al. Indole-3-propionic acid promotes hepatic stellate cells inactivation. J Transl Med 23, 253 (2025). https://doi.org/10.1186/s12967-025-06266-z
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© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
https://creativecommons.org/licenses/by/4.0/
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202503111959
https://urn.fi/URN:NBN:fi:oulu-202503111959
Tiivistelmä
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.
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.
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