Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study...Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study aimed to elucidate mechanism of mitochondria mediating HFD-induced hepatic fat accumulation.Results In the present study,yellow catfish were fed three diets with dietary fat at 6.31%(low fat;LFD,control),12.03%(middle fat;MFD)and 15.32%(high fat;HFD),respectively,for 8 weeks.High dietary fat addition raised hepatic lipid accumulation,and declined mRNA and protein levels of Parkin-dependent mitophagy,down-regulated the Parkin protein expression and the estrogen-related receptor alpha(Errα)ubiquitination,and induced Errαprotein levels;fatty acid(FA)incubation reduced Parkin-dependent mitophagy,inhibited Errαubiquitination and increased Errαprotein expression,and raised TG accumulation.Furthermore,yellow catfish hepatocytes were isolated and cultured.Nicotinamide mononucleotide,N-acetyl-L-cysteine,Parkin and errαsiRNA knockdown were used under FA incubation,respectively.Parkin downregulation mediated FA incubation-induced TG accumulation and mitoautophagic inhibition;Parkin ubiquitinated Errα,and K63 was an important ubiquitination site for deubiquitinating Parkin activity;Errαtargets fas,acca and pparγgenes,whose activation contributed to FA-induced lipogenesis and lipid accumulation.Thus,high fat diet(HFD)and FA incubation inhibited Parkin activity,suppressed mitophagy and activated Errαpathway,and induced hepatic lipogenic metabolism and lipotoxicity.Conclusions Overall,our study provided new targets against HFD-induced hepatic lipid accumulation and nonalcoholic fatty liver disease in the vertebrates.展开更多
Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular ...Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular energy metabolism,has been implicated in various cancers.but its role in MM remains unclear.Methods:ERRγexpres-sion was assessed using bioinformatics and RT-qPCR.Functional studies were conducted through siRNA-mediated ERRγknockdown and treatment with the inverse agonist GSK5182 to examine their effects on MM cell proliferation and apoptosis.Results:ERRγwas significantly upregulated in the bone marrow of MM patients,correlating with advanced clinical stages and pathological fractures.Inhibition of ERRγreduced MM cell expansion both in vitro and in vivo,while promoting mitochondrial-dependent apoptosis.Co-immunoprecipitation assays demonstrated a physical association between ERRγand P65.Inhibition of ERRγattenuated canonical nuclear factor-kappa B(NF-κB)signaling by blocking the nuclear translocation of its key effector p65.Additionally,modulation of ERRγaltered receptor activator of nuclear factor-κB ligand(RANKL)levels,implying a potential role in bone degradation observed in MM cases.Conclusion:Collectively,the data broaden understanding of ERRγ’s contribution to MM development and propose it as a viable target for therapeutic intervention.展开更多
基金funded by National Key R&D Program of China(2024YFD2402000)。
文摘Background Mitophagy is an essential cellular autophagic process which maintains mitochondrial homeostasis,but its role in high fat diet(HFD)-induced lipid accumulation is unclear in the yellow catfish.Thus,this study aimed to elucidate mechanism of mitochondria mediating HFD-induced hepatic fat accumulation.Results In the present study,yellow catfish were fed three diets with dietary fat at 6.31%(low fat;LFD,control),12.03%(middle fat;MFD)and 15.32%(high fat;HFD),respectively,for 8 weeks.High dietary fat addition raised hepatic lipid accumulation,and declined mRNA and protein levels of Parkin-dependent mitophagy,down-regulated the Parkin protein expression and the estrogen-related receptor alpha(Errα)ubiquitination,and induced Errαprotein levels;fatty acid(FA)incubation reduced Parkin-dependent mitophagy,inhibited Errαubiquitination and increased Errαprotein expression,and raised TG accumulation.Furthermore,yellow catfish hepatocytes were isolated and cultured.Nicotinamide mononucleotide,N-acetyl-L-cysteine,Parkin and errαsiRNA knockdown were used under FA incubation,respectively.Parkin downregulation mediated FA incubation-induced TG accumulation and mitoautophagic inhibition;Parkin ubiquitinated Errα,and K63 was an important ubiquitination site for deubiquitinating Parkin activity;Errαtargets fas,acca and pparγgenes,whose activation contributed to FA-induced lipogenesis and lipid accumulation.Thus,high fat diet(HFD)and FA incubation inhibited Parkin activity,suppressed mitophagy and activated Errαpathway,and induced hepatic lipogenic metabolism and lipotoxicity.Conclusions Overall,our study provided new targets against HFD-induced hepatic lipid accumulation and nonalcoholic fatty liver disease in the vertebrates.
文摘Background:Multiple myeloma(MM)remains a formidable clinical challenge due to its high relapse rate and resistance to existing therapies.Estrogen-related receptor gamma(ERRγ),a nuclear receptor critical for cellular energy metabolism,has been implicated in various cancers.but its role in MM remains unclear.Methods:ERRγexpres-sion was assessed using bioinformatics and RT-qPCR.Functional studies were conducted through siRNA-mediated ERRγknockdown and treatment with the inverse agonist GSK5182 to examine their effects on MM cell proliferation and apoptosis.Results:ERRγwas significantly upregulated in the bone marrow of MM patients,correlating with advanced clinical stages and pathological fractures.Inhibition of ERRγreduced MM cell expansion both in vitro and in vivo,while promoting mitochondrial-dependent apoptosis.Co-immunoprecipitation assays demonstrated a physical association between ERRγand P65.Inhibition of ERRγattenuated canonical nuclear factor-kappa B(NF-κB)signaling by blocking the nuclear translocation of its key effector p65.Additionally,modulation of ERRγaltered receptor activator of nuclear factor-κB ligand(RANKL)levels,implying a potential role in bone degradation observed in MM cases.Conclusion:Collectively,the data broaden understanding of ERRγ’s contribution to MM development and propose it as a viable target for therapeutic intervention.
