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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 LU orcid ; Romeo, Stefano and Pajukanta, Päivi , et al. (2025) In Journal of Translational Medicine 23(1).
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Apoptosis, Epigenetics, Hepatic stellate cells, Indole-3-propionic acid, Liver fibrosis, Mitochondrial metabolism
in
Journal of Translational Medicine
volume
23
issue
1
article number
253
publisher
BioMed Central (BMC)
external identifiers
  • pmid:40025530
  • scopus:85219615599
ISSN
1479-5876
DOI
10.1186/s12967-025-06266-z
language
English
LU publication?
yes
id
38909572-10e1-4fd2-8b2e-de57f20b8eb6
date added to LUP
2025-06-10 09:52:27
date last changed
2025-07-08 12:49:44
@article{38909572-10e1-4fd2-8b2e-de57f20b8eb6,
  abstract     = {{<p>Background &amp; 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/m<sup>2</sup>) 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.</p>}},
  author       = {{Ilha, Mariana and Sehgal, Ratika and Matilainen, Johanna and Rilla, Kirsi and Kaminska, Dorota and Gandhi, Shrey and Männistö, Ville and Ling, Charlotte and Romeo, Stefano and Pajukanta, Päivi and Pirinen, Eija and Virtanen, Kirsi A. and Pietiläinen, Kirsi H. and Vaittinen, Maija and Pihlajamäki, Jussi}},
  issn         = {{1479-5876}},
  keywords     = {{Apoptosis; Epigenetics; Hepatic stellate cells; Indole-3-propionic acid; Liver fibrosis; Mitochondrial metabolism}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Journal of Translational Medicine}},
  title        = {{Indole-3-propionic acid promotes hepatic stellate cells inactivation}},
  url          = {{http://dx.doi.org/10.1186/s12967-025-06266-z}},
  doi          = {{10.1186/s12967-025-06266-z}},
  volume       = {{23}},
  year         = {{2025}},
}