Ursolic acid targets secreted phosphoprotein 1 to regulate Th17 cells against non-alcoholic fatty liver disease

Zheng, Yiyuan; Zhao, Lina; Xiong, Zhekun; Huang, Chaoyuan; Yong, Qiuhong; Fang, Dan; Fu, Yugang; Gu, Simin; Chen, Chong; Li, Jiacheng; Zhu, Yingying; Liu, Jing; Liu, Fengbin; Li, Yong

doi:.0..

Original Article

Ursolic acid targets secreted phosphoprotein 1 to regulate Th17 cells against non-alcoholic fatty liver disease

Yiyuan Zheng¹, Lina Zhao^2,3, Zhekun Xiong⁴, Chaoyuan Huang^5,6, Qiuhong Yong^3,7, Dan Fang⁸, Yugang Fu¹, Simin Gu¹, Chong Chen¹, Jiacheng Li¹, Yingying Zhu¹, Jing Liu¹, Fengbin Liu^2,3

, Yong Li¹

¹Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China
²Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, China
³Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, China
⁴Department of Spleen, Stomach and Hepatobiliary, Zhongshan Hospital of Traditional Chinese Medicine, China
⁵Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, China
⁶Department of Gastroenterology, Guangdong Provincial Hospital of Chinese Medicine, China
⁷The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China
⁸Medical Affairs Department, Ton-Bridge Medical Technology Co., Ltd., Zhuhai, China

Correspondence :

Fengbin Liu ,
Tel: +86-020-36591912, Fax: +86-020-36591912, Email: liufengbin163@163.com
Yong Li ,
Tel: +86-021-56639828, Fax: +86-021-56639828, Email: liyong@shutcm.edu.cn

Received: January 18, 2024 Revised: April 12, 2024 Accepted: April 15, 2024
*Yiyuan Zheng, Lina Zhao and Zhekun Xiong contributed equally to this work.

ABSTRACT

Background/Aims
Non-alcoholic fatty liver disease (NAFLD) has become an increasingly important health challenge, with a substantial rise linked to changing lifestyles and global obesity. Ursolic acid, a natural pentacyclic triterpenoid, has been explored for its potential therapeutic effects. Given its multifunctional bioactive properties, this research further revealed the pharmacological mechanisms of ursolic acid on NAFLD.
Methods
Drug target chips and bioinformatics analysis were combined in this study to explore the potential therapeutic effects of ursolic acid on NAFLD. Molecular docking simulations, surface plasmon resonance analyses, pull-down experiments, and co-immunoprecipitation assays were used to verify the direct interactions. Gene knockdown mice were generated, and high-fat diets were used to validate drug efficacy. Furthermore, initial CD4+ T cells were isolated and stimulated to demonstrate our findings.
Results
In this study, the multifunctional extracellular matrix phosphorylated glycoprotein secreted phosphoprotein 1 (SPP1) was investigated, highlighting its capability to induce Th17 cell differentiation, amplifying inflammatory cascades, and subsequently promoting the evolution of NAFLD. In addition, this study revealed that in addition to the canonical TGF-β/IL-6 cytokine pathway, SPP1 can directly interact with ITGB1 and CD44, orchestrating Th17 cell differentiation via their joint downstream ERK signaling pathway. Remarkably, ursolic acid intervention notably suppressed the protein activity of SPP1, suggesting a promising avenue for ameliorating the immunoinflammatory trajectory in NAFLD progression.
Conclusions
Ursolic acid could improve immune inflammation in NAFLD by modulating SPP1-mediated Th17 cell differentiation via the ERK signaling pathway, which is orchestrated jointly by ITGB1 and CD44, emerging as a linchpin in this molecular cascade.

KeyWords: Non-alcoholic fatty liver disease, Ursolic acid, Secreted phosphoprotein 1, Th17 cells.