Tao Le, Yang Guangyue, Sun Tiantian, Zhu Chan, Yu Huimin, Cheng Yalan, Yang Zongguo, Xu Mingyi, Jiang Yuefeng, Zhang Wei, Wang Zhiyi, Ma Wenting, Wu Liu, Xue Dongying, Wang Dongxue, Yang Wentao, Zhao Yongjuan, Horsefield Shane, Kobe Bostjan, Zhang Zhe, Tang Zongxiang, Li Qigen, Zhai Qiwei, Dooley Steven, Seki Ekihiro, Liu Ping, Xu Jianrong, Chen Hongzhuan, Liu Cheng
Laboratory of Liver Disease, Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China; Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
Laboratory of Liver Disease, Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
J Hepatol. 2023 Apr;78(4):805-819. doi: 10.1016/j.jhep.2022.12.031. Epub 2023 Jan 18.
BACKGROUND & AIMS: Capsaicin receptor, also known as transient receptor potential vanilloid 1 (TRPV1), is involved in pain physiology and neurogenic inflammation. Herein, we discovered the presence of TRPV1 in hepatic stellate cells (HSCs) and aimed to delineate its function in this cell type and liver fibrosis.
TRPV1 expression was examined in liver biopsies from patients with liver fibrosis using quantitative real-time PCR and immunostaining. Its contribution to liver fibrosis was examined in Trpv1 mice, upon lentiviral delivery of the TRPV1 gene, and in human and mouse primary HSCs, using patch clamp, intracellular Ca mobilization determination, FACS analyses and gain/loss of function experiments. Binding of sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) to TRPV1 was determined using mass spectrometry, co-immunoprecipitation, surface plasmon resonance, bioluminescence resonance energy transfer, and NanoBiT.
TRPV1 mRNA levels are significantly downregulated in patients with liver fibrosis and mouse models, showing a negative correlation with F stage and α-smooth muscle actin expression, a marker of HSC activation. TRPV1 expression and function decrease during HSC activation in fibrotic livers in vivo or during culture. Genetic and pharmacological inhibition of TRPV1 in quiescent HSCs leads to NF-κB activation and pro-inflammatory cytokine production. TRPV1 requires binding of its N-terminal ankyrin repeat domain to the TIR-His583 (Toll/interleukin-1 receptor) domain of SARM1 to prevent HSCs from pro-inflammatory activation. Trpv1 mice display increased HSC activation and more severe liver fibrosis, whereas TRPV1 overexpression is antifibrotic in various disease models.
The antifibrotic properties of TRPV1 are attributed to the prevention of HSC activation via the recruitment of SARM1, which could be an attractive therapeutic strategy against liver fibrosis.
We identified the neuronal channel protein TRPV1 as a gatekeeper of quiescence in hepatic stellate cells, a key driver of liver fibrogenesis and chronic liver disease. Physiologically expressed in healthy liver and consistently downregulated during liver fibrosis development, its therapeutic re-expression is expected to have few side effects, making it an attractive target diagnostic tool and drug candidate for industry and clinicians.
辣椒素受体，也称为瞬时受体电位香草酸亚型1（TRPV1），参与疼痛生理和神经源性炎症。在此，我们发现肝星状细胞（HSC）中存在TRPV1，并旨在阐明其在这种细胞类型和肝纤维化中的功能。
使用定量实时PCR和免疫染色检测肝纤维化患者肝活检组织中TRPV1的表达。通过慢病毒递送TRPV1基因，在Trpv1小鼠中以及在人和小鼠原代HSC中，使用膜片钳、细胞内钙动员测定、流式细胞术分析和功能获得/丧失实验，研究其对肝纤维化的作用。使用质谱、免疫共沉淀、表面等离子体共振、生物发光共振能量转移和纳米生物发光互补技术测定含无菌α和Toll/白细胞介素-1受体基序蛋白1（SARM1）与TRPV1的结合。
肝纤维化患者和小鼠模型中TRPV1 mRNA水平显著下调，与F分期和HSC活化标志物α-平滑肌肌动蛋白表达呈负相关。在体内纤维化肝脏的HSC活化过程中或培养期间，TRPV1表达和功能降低。在静止HSC中对TRPV1进行基因和药理学抑制会导致NF-κB活化和促炎细胞因子产生。TRPV1需要其N端锚蛋白重复结构域与SARM1的TIR-His583（Toll/白细胞介素-1受体）结构域结合，以防止HSC发生促炎活化。Trpv1小鼠表现出HSC活化增加和更严重的肝纤维化，而在各种疾病模型中TRPV1过表达具有抗纤维化作用。
TRPV1的抗纤维化特性归因于通过募集SARM1来预防HSC活化，这可能是一种有吸引力的抗肝纤维化治疗策略。
我们确定神经元通道蛋白TRPV1是肝星状细胞静止状态的守门人，肝星状细胞是肝纤维化和慢性肝病的关键驱动因素。在健康肝脏中生理性表达，在肝纤维化发展过程中持续下调，其治疗性重新表达预计副作用较少，使其成为工业界和临床医生有吸引力的靶点、诊断工具和药物候选物。
