作者: Seuwen, Klaus ; Pobiarzyn, Piotr ; Biernacki, Karol ; Krajewski, Oliwier ; Smoleński, Ryszard T. ; Opiełka, Mikołaj ; Urbanowicz, Krzysztof ; Rutkowska, Aleksandra ; Smoleński, Ryszard T ; Demkowicz, Sebastian ; Karaszewski, Bartosz ; Konieczna-Wolska, Klaudia ; Klimaszewska, Joanna ; Caratis, Fionä

Research indicates a role for EBI2 receptor in remyelination, demonstrating that its deficiency or antagonism inhibits this process. However, activation of EBI2 with its endogenous ligand, oxysterol 7α,25-dihydroxycholesterol (7α,25OHC), does not enhance remyelination beyond the levels observed in spontaneously remyelinating tissue. We hypothesized that the short half-life of the natural ligand might explain this lack of beneficial effects and tested a synthetic analogue, CF₃-7α,25OHC, in the cuprizone model. The data showed that extending the bioavailability of 7α,25OHC is sufficient to accelerate remyelination in vivo. Moreover, the analogue, in contrast to the endogenous ligand, upregulated brain expression of Ebi2 and the synthesis of 15 lipids in the mouse corpus callosum. Mechanistically, the increased concentration of oxysterol likely disrupted its gradient in demyelinated areas of the brain, leading to the dispersion of infiltrating EBI2-expressing immune cells rather than their accumulation in demyelinated regions. Remarkably, the analogue CF₃-7α,25OHC markedly decreased the lymphocyte and monocyte counts mimicking the key mechanism of action of some of the most effective disease-modifying therapies for multiple sclerosis. Furthermore, the Cd4+ transcripts in the cerebellum and CD4+ cell number in the corpus callosum were reduced compared to vehicle-treated mice. These findings suggest a mechanism by which EBI2/7α,25OHC signalling modulates the immune response and accelerates remyelination in vivo.

2020-07-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

7α,25-Dihydroxycholesterol Suppresses Hepatocellular Steatosis through GPR183/EBI2 in Mouse and Human Hepatocytes

3区 · 医学

Article

作者: Huang, Jin ; Lee, Seung-Jin ; Im, Dong-Soon ; Kang, Saeromi ; Choi, Man Ho

Nonalcoholic fatty liver disease is a chronic inflammatory liver disease. It is associated with obesity and type 2 diabetes. Oxycholesterols are metabolites of cholesterol, and several of them can act on the G protein-coupled receptor, G protein-coupled receptor 183 (GPR183)/Epstein-Barr virus-induced gene 2. We found expression of GPR183 in human hepatoma cell lines and in vivo induction of GPR183 expression in mouse livers after high-fat diet feeding. Therefore, the role of oxycholesterols and GPR183 in hepatocytes was studied using a model of hepatic steatosis induced by liver X receptor (LXR) activation. LXR activation by T0901317 resulted in fat accumulation in Hep3B human hepatoma cells. This lipid accumulation was inhibited by 7α,25-dihydroxycholesterol, the most potent agonist of GPR183. The protective effects of 7α,25-dihydroxycholesterol were suppressed by a specific GPR183 antagonist, NIBR189 [(2E)-3-(4-Bromophenyl)-1-[4-4-methoxybenzoyl)-1-piperazinyl]-2-propene-1-one]. T0901317 treatment induced expression of the major transcription factor for lipogenesis, sterol regulatory element-binding protein 1c (SREBP-1c). 7α,25-Dihydroxycholesterol inhibited the induction of SREBP-1c proteins in a GPR183-dependent manner. Using inhibitors specific for intracellular signaling molecules, 7α,25-dihydroxycholesterol-induced suppression of hepatocellular steatosis was shown to be mediated through G_i/o proteins, p38 mitogen-activated protein kinases, phosphoinositide 3-kinase, and AMP-activated protein kinase. In addition, the inhibitory effect of 7α,25-dihydroxycholesterol was validated in HepG2 cells and primary mouse hepatocytes. Therefore, the present report suggests that 7α,25-dihydroxycholesterol-GPR183 signaling may suppress hepatocellular steatosis in the liver. SIGNIFICANCE STATEMENT: Oxycholesterols, which are metabolites of cholesterol, act on the G protein-coupled receptor, G protein-coupled receptor 183 (GPR183)/Epstein-Barr virus-induced gene 2, which is expressed in human hepatoma cell lines, and its expression is induced in vivo in mouse livers after high-fat diet feeding. Activation of GPR183 inhibits fat accumulation in primary mouse hepatocytes and HepG2 cells through G_i/o proteins, p38 mitogen-activated protein kinases, phosphoinositide 3-kinase, and AMP-activated protein kinase.

2018-05-01·Redox Biology

Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression

Article

作者: Tamborra, Rosanna ; Facciorusso, Antonio ; Serviddio, Gaetano ; Blonda, Maria ; Poli, Giuseppe ; Avolio, Carlo ; Iannelli, Giuseppina ; di Bello, Giorgia ; Vendemiale, Gianluigi ; Iuliano, Luigi ; Villani, Rosanna ; Bellanti, Francesco

The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury.

100 项与 EBI2 agonists(Euroscreen) 相关的药物交易

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