Lactate Protects Microglia and Neurons from Oxygen–Glucose Deprivation/Reoxygenation

Tassinari, Isadora D’Ávila; Rodrigues, Fernanda da Silva; Bertram, Craig; Mendes-da-Cruz, Daniella Arêas; Guedes, Renata Padilha; Paz, Ana Helena; Bambini-Junior, Victorio; de Fraga, Luciano Stürmer

doi:10.1007/s11064-024-04135-7

Cited by 2 publications

(1 citation statement)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to using the GPR81 KO mice, DHBA, a widely used GPR81 agonist (Vohra et al 2022 ; Ohno et al 2018 ; Tassinari et al 2024 ), was used in the present study to investigate the pathological significance of GPR81. A previous study suggested that the carboxyl group, the 3-hydroxyl group, and the 5-hydroxyl group of DHBA are crucial for the molecular interactions between DHBA and GPR81, and treatment with DHBA inhibited the release of free fatty acid and glycerol in adipocytes, but the antilipolytic effects of DHBA were abolished in GPR81-deficient adipocytes (Liu et al 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Deletion of GPR81 activates CREB/Smad7 pathway and alleviates liver fibrosis in mice

Zhi,

Fan,

Liu

et al. 2024

Mol Med

View full text Add to dashboard Cite

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-β1)-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-β1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation. Results CCl4 exposure or TGF-β1 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-β1, 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-β1-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.

show abstract