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Deletion of GPR81 activates CREB/Smad7 pathway and alleviates liver fibrosis in mice.
Zhi, Ying; Fan, Kerui; Liu, Shuang; Hu, Kai; Zan, Xinyan; Lin, Ling; Yang, Yongqiang; Gong, Xianqiong; Chen, Kun; Tang, Li; Li, Longjiang; Huang, Jiayi; Zhang, Shujun; Zhang, Li.
Afiliación
  • Zhi Y; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
  • Fan K; Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China.
  • Liu S; Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China.
  • Hu K; Department of Anatomy, Basic Medical College, Chongqing Medical University, Chongqing, China.
  • Zan X; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
  • Lin L; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
  • Yang Y; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
  • Gong X; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
  • Chen K; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
  • Tang L; Hepatology Center, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China.
  • Li L; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
  • Huang J; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
  • Zhang S; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
  • Zhang L; Department of Pathophysiology, Basic Medical College, Chongqing Medical University, 1 Yixueyuan Road, Chongqing, 400016, China.
Mol Med ; 30(1): 99, 2024 Jul 09.
Article en En | MEDLINE | ID: mdl-38982366
ABSTRACT

BACKGROUND:

Enhanced glycolysis is a crucial metabolic event that drives the development of liver fibrosis, but the molecular mechanisms have not been fully understood. Lactate is the endproduct of glycolysis, which has recently been identified as a bioactive metabolite binding to G-protein-coupled receptor 81 (GPR81). We then questioned whether GPR81 is implicated in the development of liver fibrosis.

METHODS:

The level of GPR81 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and in transforming growth factor beta 1 (TGF-ß1)-activated hepatic stellate cells (HSCs) LX-2. To investigate the significance of GPR81 in liver fibrosis, wild-type (WT) and GPR81 knockout (KO) mice were exposed to CCl4, and then the degree of liver fibrosis was determined. In addition, the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) was supplemented in CCl4-challenged mice and TGF-ß1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation.

RESULTS:

CCl4 exposure or TGF-ß1 stimulation significantly upregulated the expression of GPR81, while deletion of GPR81 alleviated CCl4-induced elevation of aminotransferase, production of pro-inflammatory cytokines, and deposition of collagen. Consistently, the production of TGF-ß1, the expression of alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1), as well as the elevation of hydroxyproline were suppressed in GPR81 deficient mice. Supplementation with DHBA enhanced CCl4-induced liver fibrogenesis in WT mice but not in GPR81 KO mice. DHBA also promoted TGF-ß1-induced LX-2 activation. Mechanistically, GPR81 suppressed cAMP/CREB and then inhibited the expression of Smad7, a negative regulator of Smad3, which resulted in increased phosphorylation of Smad3 and enhanced activation of HSCs.

CONCLUSION:

GPR81 might be a detrimental factor that promotes the development of liver fibrosis by regulating CREB/Smad7 pathway.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tetracloruro de Carbono / Transducción de Señal / Proteína de Unión a Elemento de Respuesta al AMP Cíclico / Ratones Noqueados / Receptores Acoplados a Proteínas G / Proteína smad7 / Células Estrelladas Hepáticas / Cirrosis Hepática Límite: Animals / Humans / Male Idioma: En Revista: Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tetracloruro de Carbono / Transducción de Señal / Proteína de Unión a Elemento de Respuesta al AMP Cíclico / Ratones Noqueados / Receptores Acoplados a Proteínas G / Proteína smad7 / Células Estrelladas Hepáticas / Cirrosis Hepática Límite: Animals / Humans / Male Idioma: En Revista: Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido