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
Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
Department of Neurosurgery, University of Pennsylvania, Philadelphia, USA.
J Transl Med. 2025 Mar 1;23(1):253. doi: 10.1186/s12967-025-06266-z.
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.
A total of 116 obese individuals without type 2 diabetes (T2D) (age 46.8 ± 9.3 years; BMI: 42.7 ± 5.0 kg/m) 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.
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.
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.
我们之前报道过，肝纤维化患者血清中肠道来源的色氨酸代谢产物吲哚 - 3 - 丙酸（IPA）水平较低。现在，我们探讨了肥胖个体肝脏中与血清IPA水平相关的转录组和DNA甲基化组，以及IPA在体外使肝星状细胞（HSC）表型转变为失活状态的作用。
纳入了来自库奥皮奥肥胖手术（KOBS）研究的116例无2型糖尿病（T2D）的肥胖个体（年龄46.8±9.3岁；BMI：42.7±5.0kg/m²），他们接受了减肥手术。使用液相色谱 - 质谱法测量循环IPA水平，通过全RNA测序进行肝脏转录组学分析，并使用Infinium HumanMethylation450 BeadChip进行DNA甲基化分析。使用人肝星状细胞（LX - 2）进行体外实验。
血清IPA水平与肝脏中富含凋亡、线粒体自噬和长寿途径的基因表达相关。AKT丝氨酸/苏氨酸激酶1（AKT1）是肝脏转录本和DNA甲基化谱中共同且最主要的相互作用基因。IPA处理可诱导凋亡、降低线粒体呼吸，并通过调节已知调节LX - 2细胞纤维化、凋亡和存活的基因表达来改变细胞形态和线粒体动力学。
总之，这些数据支持IPA具有合理的治疗作用，可能诱导凋亡并使HSC表型向失活状态转变，从而通过干扰HSC激活和线粒体代谢来扩展抑制肝纤维化的可能性。
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