Adiponectin receptor 1(Adipor1)deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice.Additional emerging evidence indicates tha...Adiponectin receptor 1(Adipor1)deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice.Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic(pTh17)and non-pathogenic(npTh17)cells,with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions.In the current study,we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and induced mitochondrial dysfunction in pTh17 cells.RNA sequencing demonstrated a significant increase in the expression levels of Fundc1,a gene related to mitochondrial function,in Adipor1-deficient CD4^(+)T cells.Fundc1 knockdown in Adipor1-deficient CD4^(+)T cells partially reversed the effects of Adipor1 deficiency on mitochondrial function and pTh17 differentiation.In conclusion,the current study demonstrated a novel role of Adipor1 in regulating mitochondrial function via Fundc1 to promote pTh17 cell differentiation,providing some insight into potential therapeutic targets for autoimmune and inflammatory diseases.展开更多
Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Ac...Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.展开更多
基金the National Natural Science Foundation of China(Grant No.82071827)the Jiangsu Province Natural Science Foundation(Grant No.BK20210963).
文摘Adiponectin receptor 1(Adipor1)deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice.Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic(pTh17)and non-pathogenic(npTh17)cells,with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions.In the current study,we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and induced mitochondrial dysfunction in pTh17 cells.RNA sequencing demonstrated a significant increase in the expression levels of Fundc1,a gene related to mitochondrial function,in Adipor1-deficient CD4^(+)T cells.Fundc1 knockdown in Adipor1-deficient CD4^(+)T cells partially reversed the effects of Adipor1 deficiency on mitochondrial function and pTh17 differentiation.In conclusion,the current study demonstrated a novel role of Adipor1 in regulating mitochondrial function via Fundc1 to promote pTh17 cell differentiation,providing some insight into potential therapeutic targets for autoimmune and inflammatory diseases.
基金the financial support from the National Natural Science Foundation of China(Nos.91853106,81870420 and 82070590)the Program for Guangdong Introducing Innovative and Enterpre-neurial Teams(No.2016ZT06Y337,China)+3 种基金The Fundamental Research Funds for the Central Universities(No.19ykzd25,China)National Key Research and Development Program(No.2017YFE0109900,China)Special Topics of General Projects of Guangzhou Science and Technology Plan of China(201904010075)CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-074,China)。
文摘Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.
