Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis.However,which molecule regulates macrophage polarizatio...Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis.However,which molecule regulates macrophage polarization in NAFLD remains unclear.Herein,we showed NAFLD mice exhibited increased 17β-hydroxysteroid dehydrogenase type 7(17β-HSD7)expression in hepatic macrophages concomitantly with elevated M1 polarization.Single-cell RNA sequencing on hepatic non-parenchymal cells isolated from wild-type littermates and macrophage-17β-HSD7 knockout mice fed with high fat diet(HFD)for 6 weeks revealed that lipid metabolism pathways were notably changed.Furthermore,17β-HSD7 deficiency in macrophages attenuated HFD-induced hepatic steatosis,insulin resistance and liver injury.Mechanistically,17β-HSD7 triggered NLRP3 inflammasome activation by increasing free cholesterol content,thereby promoting M1 polarization of macrophages and the secretion of pro-inflammatory cytokines.In addition,to help demonstrate that 17β-HSD7 is a potential drug target for NAFLD,fenretinide was screened out from an FDA-approved drug library based on its 17β-HSD7 dehydrogenase inhibitory activity.Fenretinide dose-dependently abrogated macrophage polarization and pro-inflammatory cytokines production,and subsequently inhibited fat deposition in hepatocytes co-cultured with macrophages.In conclusion,our findings suggest that blockade of 17β-HSD7 signaling by fenretinide would be a drug repurposing strategy for NAFLD treatment.展开更多
Most therapeutic protocols for child cancers use cytotoxic agents which have a narrow therapeutic index,and resulting in severe acute and chronic toxicities to normal tissues. Despite the fact that most child cancer p...Most therapeutic protocols for child cancers use cytotoxic agents which have a narrow therapeutic index,and resulting in severe acute and chronic toxicities to normal tissues. Despite the fact that most child cancer patients achieve complete remission after chemotherapy,death still occurs due to relapse of persistent minimal residual disease(MRD) which remaining after initial cytotoxic chemotherapy. Advanced neuroblastoma(NB) is a leading cause of cancer deaths in young children. Retinoids are an important component of advanced NB therapy at the stage of MRD,yet half of all patients treated with 13-cis-retinoic acid still relapse and die. More effective combination therapies,with a lower side-effect profile,are required to improve outcomes for NB. Fenretinide or N-4-hydroxyphenyl retinamide is a synthetic derivative of retinoic acid which works on cancer cells through nuclear receptor-dependent and-independent signalling mechanisms. Moreover,several histone deacetylase inhibitors have entered early phase trials,and,suberoylanilide hydroxamic acid has been approved for use in adult cutaneous T cell lymphoma. A number of studies suggest that retinoid signal activation is necessary for histone deacetylase inhibitor activity. A better understanding of their mechanism of actions will lead to more evidence-based retinoid combination therapies.展开更多
基金supported by the National Nature Science Foundation of China(Nos.82173872 and 81872663)。
文摘Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis.However,which molecule regulates macrophage polarization in NAFLD remains unclear.Herein,we showed NAFLD mice exhibited increased 17β-hydroxysteroid dehydrogenase type 7(17β-HSD7)expression in hepatic macrophages concomitantly with elevated M1 polarization.Single-cell RNA sequencing on hepatic non-parenchymal cells isolated from wild-type littermates and macrophage-17β-HSD7 knockout mice fed with high fat diet(HFD)for 6 weeks revealed that lipid metabolism pathways were notably changed.Furthermore,17β-HSD7 deficiency in macrophages attenuated HFD-induced hepatic steatosis,insulin resistance and liver injury.Mechanistically,17β-HSD7 triggered NLRP3 inflammasome activation by increasing free cholesterol content,thereby promoting M1 polarization of macrophages and the secretion of pro-inflammatory cytokines.In addition,to help demonstrate that 17β-HSD7 is a potential drug target for NAFLD,fenretinide was screened out from an FDA-approved drug library based on its 17β-HSD7 dehydrogenase inhibitory activity.Fenretinide dose-dependently abrogated macrophage polarization and pro-inflammatory cytokines production,and subsequently inhibited fat deposition in hepatocytes co-cultured with macrophages.In conclusion,our findings suggest that blockade of 17β-HSD7 signaling by fenretinide would be a drug repurposing strategy for NAFLD treatment.
文摘Most therapeutic protocols for child cancers use cytotoxic agents which have a narrow therapeutic index,and resulting in severe acute and chronic toxicities to normal tissues. Despite the fact that most child cancer patients achieve complete remission after chemotherapy,death still occurs due to relapse of persistent minimal residual disease(MRD) which remaining after initial cytotoxic chemotherapy. Advanced neuroblastoma(NB) is a leading cause of cancer deaths in young children. Retinoids are an important component of advanced NB therapy at the stage of MRD,yet half of all patients treated with 13-cis-retinoic acid still relapse and die. More effective combination therapies,with a lower side-effect profile,are required to improve outcomes for NB. Fenretinide or N-4-hydroxyphenyl retinamide is a synthetic derivative of retinoic acid which works on cancer cells through nuclear receptor-dependent and-independent signalling mechanisms. Moreover,several histone deacetylase inhibitors have entered early phase trials,and,suberoylanilide hydroxamic acid has been approved for use in adult cutaneous T cell lymphoma. A number of studies suggest that retinoid signal activation is necessary for histone deacetylase inhibitor activity. A better understanding of their mechanism of actions will lead to more evidence-based retinoid combination therapies.
