Effect of Protease-Activated Receptor 2 inhibition by 1-Piperidinepropionic acid in lipid accumulation, inflammation and hepatocellular carcinoma development

IF 4 3区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Digestive and Liver Disease Pub Date : 2025-02-01 DOI:10.1016/j.dld.2025.01.009

P. Guerra , G. Villano , C.M. Rejano-Gordillo , M. Ruvoletto , A. Biasiolo , S. Quarta , P. Peña-SanFelix , S. De Siervi , S. Cagnin , C. Turato , M.L. Martínez-Chantar , P. Pontisso , A. Martini

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引用次数: 0

Abstract

Introduction

Hepatocellular carcinoma (HCC) and Metabolic-Associated Steatohepatitis (MASH) are major challenges in modern hepatology. 1-Piperidinepropionic Acid (1-PPA) is a novel inhibitor of Protease-Activated Receptor 2 (PAR2), which is involved in inflammation, lipid accumulation and tumour development. This study aims to evaluate the effect of 1-PPA on liver steatosis, inflammation and HCC development.

Materials

C57BL/6J mice transgenic overexpressing SerpinB3 (C57/TG), fed on a CDAA diet and injected with diethylnitrosamine (DEN) were divided into two groups (n=8 each) and treated with 1-PPA or placebo. HCC development was confirmed by liver histology. Microsomal triglyceride transfer protein (MTP) activity was quantified in liver tissue using a specific assay. qPCR of macrophage M2-polarization markers was carried out. Human liver organoids were cultured with Oleic Acid and SB3, and treated with 1-PPA and lomitapide, an inhibitor of VLDL export. Lipid and ROS accumulation was quantified using BodiPY and MitoSOX respectively.

Results

C57/TG mice treated with 1-PPA developed a lower mean number of nodules (1.5 vs 5, p < 0.05), a reduced mean tumoral mass (0.04 vs 0.1 g, p < 0.01) and a blunted expression of M2-polarization macrophage markers. MTP activity was increased in the liver of mice treated with 1-PPA. Human liver organoids showed a significant increase in lipid and ROS accumulation after Oleic Acid administration. Treatment with 1-PPA significantly lower lipid and ROS accumulation, however contemporary treatment with lomitapide reverted this effect, suggesting a role in VLDL export.

Conclusion

1-PPA treatment reduced HCC development by reducing lipid accumulation and M2-macrophage polarization in a mouse model of NASH-induced liver carcinogenesis. 1-PPA treatment reduced lipid accumulation by stimulating VLDL formation and secretion both in a mouse model of MASH-induced liver carcinogenesis and in human liver organoids.

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来源期刊

Digestive and Liver Disease 医学-胃肠肝病学

CiteScore

6.10

自引率

2.20%

发文量

632

审稿时长

19 days

期刊介绍： Digestive and Liver Disease is an international journal of Gastroenterology and Hepatology. It is the official journal of Italian Association for the Study of the Liver (AISF); Italian Association for the Study of the Pancreas (AISP); Italian Association for Digestive Endoscopy (SIED); Italian Association for Hospital Gastroenterologists and Digestive Endoscopists (AIGO); Italian Society of Gastroenterology (SIGE); Italian Society of Pediatric Gastroenterology and Hepatology (SIGENP) and Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD). Digestive and Liver Disease publishes papers on basic and clinical research in the field of gastroenterology and hepatology. Contributions consist of: Original Papers Correspondence to the Editor Editorials, Reviews and Special Articles Progress Reports Image of the Month Congress Proceedings Symposia and Mini-symposia.