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
Publisher: Springer Science and Business Media LLC
: LONDON
: 2025
: Journal of Translational Medicine
: Journal of Translational Medicine
: J TRANSL MED
: 253
: 23
: 1
: 18
: 1479-5876
DOI: https://doi.org/10.1186/s12967-025-06266-z
: https://doi.org/10.1186/s12967-025-06266-z
: https://research.utu.fi/converis/portal/detail/Publication/491419792
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.
ConclusionIn
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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M.I. was supported by the Health from Science (TERVA, 404030) project. R.S. was supported by the GenomMed Doctoral Programme, co-funded by the Horizon 2020 Framework Programme of the European Union (Marie Skłodowska Curie grant agreement no. 740264). J.M. and K.R. were supported by the Academy of Finland GeneCellNano Flagship (grant 337120) and the Jane and Aatos Erkko Foundation. V.M. was supported by a grant from the Finnish Medical Foundation. D.K. was supported by the Academy of Finland (contract no. 316458). C.L. was granted by the Swedish Research Council, Region Skåne (ALF), Novo Nordisk Foundation, EFSD, The Swedish Diabetes Foundation, Påhlsson Foundation, EXODIAB, and the Swedish Foundation for the Strategic Research (Dnr IRC15-0067) P.P. was supported by the National Institutes of Health (NIH) grants R01HL170604, R01DK132775 and R01HG010505. E.P. Academy of Finland TERVA funding; 335445 and 314455, Academy of Finland Profi6 336449 funding. Finnish Medical Foundation. K.A.V. Academy of Finland (grant numbers 314456, 335446), Finnish Medical Foundation. K.H.P. Academy of Finland, grant numbers 335443, 314383, 272376, 266286; Finnish Medical Foundation; Gyllenberg Foundation; Novo Nordisk Foundation, grant numbers NNF20OC0060547, NNF17OC0027232, NNF10OC1013354; Finnish Diabetes Research Foundation; University of Helsinki; Government Research Funds; Helsinki University Hospital. M.V. was supported by the Academy of Finland (Contract no. 324494). J.P. Kuopio Obesity Surgery Study was supported by the Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005–2019), and the Academy of Finland grant 138006 to KOBS study. These analyses were supported by Academy of Finland TERVA funding; 314454 and 335444, and a related grant from the Finnish Medical Foundation.
