Non-alcoholic fatty liver disease(NAFLD)patients have multiple metabolic distur-bances,with markedly elevated levels of lactate.Lactate accumulations play pleiotropic roles in disease progression through metabolic rea...Non-alcoholic fatty liver disease(NAFLD)patients have multiple metabolic distur-bances,with markedly elevated levels of lactate.Lactate accumulations play pleiotropic roles in disease progression through metabolic rearrangements and epigenetic modifications.Mono-carboxylate transporter 4(MCT4)is highly expressed in hepatocytes and responsible for trans-porting intracellular lactate out of the cell.To explore whether elevated MCT4 levels played any role in NAFLD development,we overexpressed and silenced MCT4 in hepatocytes and per-formed a comprehensive in vitro and in vivo analysis.Our results revealed that MCT4 overex-pression down-regulated the genes for lipid synthesis while up-regulating the genes involved in lipid catabolism.Conversely,silencing MCT4 expression or inhibiting MCT4 expression led to the accumulation of intracellular lipid and glucose metabolites,resulting in hepatic steatosis.In a mouse model of NAFLD,we found that exogenous MCT4 overexpression significantly reduced lipid metabolism and alleviated hepatocellular steatosis.Mechanistically,MCT4 alle-viated hepatic steatosis by regulating a group of hub genes such as Arg2,Olr1,Cd74,Mmp8,Irf7,Spp1,and Apoe,which in turn impacted multiple pathways involved in lipid metabolism and inflammatory response,such as PPAR,HIF-1,TNF,IL-17,PI3K-AKT,Wnt,and JAK-STAT.Collectively,our results strongly suggest that MCT4 may play an important role in regulating lipid metabolism and inflammation and thus serve as a potential therapeutic target for NAFLD.展开更多
Background:Hypoxic microenvironment is immunosuppressive and protu-morigenic,and elevated lactate is an intermediary in the modulation of immune responses.However,as critical lactate transporters,the role of SLC16A1 a...Background:Hypoxic microenvironment is immunosuppressive and protu-morigenic,and elevated lactate is an intermediary in the modulation of immune responses.However,as critical lactate transporters,the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated.Methods:Gene expression in low‐and high‐grade glioma(LGG and GBM)was evaluated with TCGA database.The TISIDB,TIMER and CIBERSORT databases were utilized for the analysis of the correlation between SLC16A1 or SLC16A3 and immunocyte infiltration as well as immune checkpoints.Results:Compared with normal tissues,a significant increase of both SLC16A1 and SLC16A3 was found in LGG and GBM,and closely related to the poor prognosis only in LGG.Cancer SEA indicated that SLC16A1 was involved in hypoxia while SLC16A3 contributed to metastasis and inflamma-tion in glioma.The SLC16A3 expression was significantly correlated with neutrophil activation by GO analysis.TISCH showed the distribution of SLC16A1 on glioma cells and SLC16A3 on immune cells,which was correlated to tumor‐associated macrophages and neutrophils that are immunosuppressive.SLC16A1 and SLC16A3 were identified to tightly interacted with diverse immune checkpoints(especially PD1,PD‐L1,PD‐L2,Tim‐3)and immunosuppressive factors(TGF‐βand IL‐10)in glioma.Furthermore,SLC16A3 had a positive correlation to activation markers of tumor‐associated neutrophils and chemokines such as CCL2,CCL22,CXCR2,CXCR4 in LGG and CCL7,CCL20 CXCL8 in GBM,which could enhance infiltration of immunosuppressive cells to the tumor microenvironment.Conclusion:In general,our results suggest that SLC16A1 and SLC16A3 act as a bridge between tumor metabolism and immunity by promoting immuno-suppressive cell infiltration,which contributes to immune evasion and a worse prognosis in glioma.Targeting SLC16A1 and SLC16A3 may provide novel therapeutic strategy for immunotherapy in glioma.展开更多
基金supported in part by research grants from the Natural Science Foundation of China(No.82102696 to J.F.)the Chongqing Natural Science Foundation of China(No.2024NSCQ-MSX0073 to J.F.)+3 种基金the US National Institutes of Health(No.CA226303 to T.C.H.)supported in part by The University of Chicago Cancer Center Support Grant(No.P30CA014599)the National Center for Advancing Translational Sciences of the US National Institutes of Health(No.UL1 TR000430)T.C.H.was supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘Non-alcoholic fatty liver disease(NAFLD)patients have multiple metabolic distur-bances,with markedly elevated levels of lactate.Lactate accumulations play pleiotropic roles in disease progression through metabolic rearrangements and epigenetic modifications.Mono-carboxylate transporter 4(MCT4)is highly expressed in hepatocytes and responsible for trans-porting intracellular lactate out of the cell.To explore whether elevated MCT4 levels played any role in NAFLD development,we overexpressed and silenced MCT4 in hepatocytes and per-formed a comprehensive in vitro and in vivo analysis.Our results revealed that MCT4 overex-pression down-regulated the genes for lipid synthesis while up-regulating the genes involved in lipid catabolism.Conversely,silencing MCT4 expression or inhibiting MCT4 expression led to the accumulation of intracellular lipid and glucose metabolites,resulting in hepatic steatosis.In a mouse model of NAFLD,we found that exogenous MCT4 overexpression significantly reduced lipid metabolism and alleviated hepatocellular steatosis.Mechanistically,MCT4 alle-viated hepatic steatosis by regulating a group of hub genes such as Arg2,Olr1,Cd74,Mmp8,Irf7,Spp1,and Apoe,which in turn impacted multiple pathways involved in lipid metabolism and inflammatory response,such as PPAR,HIF-1,TNF,IL-17,PI3K-AKT,Wnt,and JAK-STAT.Collectively,our results strongly suggest that MCT4 may play an important role in regulating lipid metabolism and inflammation and thus serve as a potential therapeutic target for NAFLD.
基金Ningbo Health Branding Subject Fund,Grant/Award Number:PPXK2018‐04Zhejiang Medical and Health Science&Technology Project,Grant/Award Number:2020KY826National Natural Science Foundation of China,Grant/Award Number:81903144。
文摘Background:Hypoxic microenvironment is immunosuppressive and protu-morigenic,and elevated lactate is an intermediary in the modulation of immune responses.However,as critical lactate transporters,the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated.Methods:Gene expression in low‐and high‐grade glioma(LGG and GBM)was evaluated with TCGA database.The TISIDB,TIMER and CIBERSORT databases were utilized for the analysis of the correlation between SLC16A1 or SLC16A3 and immunocyte infiltration as well as immune checkpoints.Results:Compared with normal tissues,a significant increase of both SLC16A1 and SLC16A3 was found in LGG and GBM,and closely related to the poor prognosis only in LGG.Cancer SEA indicated that SLC16A1 was involved in hypoxia while SLC16A3 contributed to metastasis and inflamma-tion in glioma.The SLC16A3 expression was significantly correlated with neutrophil activation by GO analysis.TISCH showed the distribution of SLC16A1 on glioma cells and SLC16A3 on immune cells,which was correlated to tumor‐associated macrophages and neutrophils that are immunosuppressive.SLC16A1 and SLC16A3 were identified to tightly interacted with diverse immune checkpoints(especially PD1,PD‐L1,PD‐L2,Tim‐3)and immunosuppressive factors(TGF‐βand IL‐10)in glioma.Furthermore,SLC16A3 had a positive correlation to activation markers of tumor‐associated neutrophils and chemokines such as CCL2,CCL22,CXCR2,CXCR4 in LGG and CCL7,CCL20 CXCL8 in GBM,which could enhance infiltration of immunosuppressive cells to the tumor microenvironment.Conclusion:In general,our results suggest that SLC16A1 and SLC16A3 act as a bridge between tumor metabolism and immunity by promoting immuno-suppressive cell infiltration,which contributes to immune evasion and a worse prognosis in glioma.Targeting SLC16A1 and SLC16A3 may provide novel therapeutic strategy for immunotherapy in glioma.
