Background:Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease(MASLD).We aimed to investig...Background:Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease(MASLD).We aimed to investigate the causative role and molecular mechanisms of P.copri in pediatric MASLD.Methods:C57BL/6 J mice aged 3 weeks were fed a high-fat diet(HFD)and orally administered with P.copri for 5 weeks.We assessed the key features of MASLD and the gut microbiota profile.By untargeted metabolomics on mouse fecal samples and the supernatant from P.copri culture,we identified P.copriderived metabolite and tested its effects in vitro.Results:In HFD-fed mice,administration of P.copri significantly promoted liver steatosis.Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD+P.copri group compared with those in the livers from the HFD group.In addition,P.copri reduced gut microbial diversity,increased the proportion of Firmicutes and decreased Bacteroidota.Importantly,5-aminopentanoic acid(5-AVA)was significantly enriched in both mouse feces from the HFD+P.copri group and the culture supernatant of P.copri.In vitro,5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes.Mechanistically,P.copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake,while also reducing hepatic very-low-density lipoprotein export.Conclusions:Our findings demonstrated that P.copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA,suggesting its potential as a therapeutic target for the management of pediatric MASLD.展开更多
Background:Metabolic dysfunction-associated steatotic liver disease(MASLD)is one of the leading causes of chronic liver disease worldwide.Recently,short-chain fatty acids(SCFAs),as metabolites of intesti-nal flora,hav...Background:Metabolic dysfunction-associated steatotic liver disease(MASLD)is one of the leading causes of chronic liver disease worldwide.Recently,short-chain fatty acids(SCFAs),as metabolites of intesti-nal flora,have been found to participate in the progression of MASLD.Sodium butyrate(NaB),one of the most important SCFAs,shows therapeutic potentials in MASLD and its mechanisms have not been fully understood.The present study aimed to investigate the effects of NaB on metabolic dysfunction-associated steatohepatitis(MASH)associated fibrosis as well as the underlying mechanisms.Methods:Male Sprague-Dawley rats were randomly assigned to three groups:(i)control group,stan-dard chow for 24 weeks;(ii)HFD group,high-fat and high-cholesterol diet(HFD)for 24 weeks;and(iii)HFD+NaB group,HFD for 24 weeks and NaB gavage for the last 16 weeks.Body weight,liver index(liver weight/body weight×100%),serum parameters,and liver histology were analyzed to evaluate MASH and fibrosis severity.AML12,RAW264.7 and LX2 cell lines were used for in vitro study.Results:Compared to MASH rats with fibrosis induced by 24-week HFD,NaB intervention alleviated the degree of hepatic steatosis,inflammation,hepatocyte ballooning,and fibrosis.Further mechanistic study showed that NaB supplementation significantly decreased miR-155-5p level in the liver and the serum of MASH rats,and the inhibition effects of miR-155-5p on suppressor of cytokine signaling 1(SOCS1)in both hepatocytes and hepatic stellate cells(HSCs)were blunted when they were treated with NaB.Fur-thermore,NaB also significantly decreased the production of platelet-derived growth factor-BB(PDGF-BB),a pro-fibrotic mediator,in hepatocytes.NaB treatment on AML12 cells markedly impaired the prolifera-tion ability of co-cultured LX2 cells.Moreover,NaB intervention or miR-155-5p mimics also interferes extracellular regulated protein kinases signaling in LX2 cells.Conclusions:NaB intervention inhibited HSCs activation via miR-155-5p/SOCS1/PDGF signaling pathway and consequently relieved fibrosis in MASH rats.NaB might be a potential agent for the treatment of fibrosis in patients with MASH.展开更多
基金supported by grants from the National Key R&D Program of China(2022YFA1305600)National Natural Science Foundation of China(82100950,82470602,and 82470600)Natural Science Foundation of Shanghai(23ZR1452600)。
文摘Background:Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease(MASLD).We aimed to investigate the causative role and molecular mechanisms of P.copri in pediatric MASLD.Methods:C57BL/6 J mice aged 3 weeks were fed a high-fat diet(HFD)and orally administered with P.copri for 5 weeks.We assessed the key features of MASLD and the gut microbiota profile.By untargeted metabolomics on mouse fecal samples and the supernatant from P.copri culture,we identified P.copriderived metabolite and tested its effects in vitro.Results:In HFD-fed mice,administration of P.copri significantly promoted liver steatosis.Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD+P.copri group compared with those in the livers from the HFD group.In addition,P.copri reduced gut microbial diversity,increased the proportion of Firmicutes and decreased Bacteroidota.Importantly,5-aminopentanoic acid(5-AVA)was significantly enriched in both mouse feces from the HFD+P.copri group and the culture supernatant of P.copri.In vitro,5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes.Mechanistically,P.copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake,while also reducing hepatic very-low-density lipoprotein export.Conclusions:Our findings demonstrated that P.copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA,suggesting its potential as a therapeutic target for the management of pediatric MASLD.
基金supported by grants from the National Natural Science Foundation of China(81873565 and 81900507).
文摘Background:Metabolic dysfunction-associated steatotic liver disease(MASLD)is one of the leading causes of chronic liver disease worldwide.Recently,short-chain fatty acids(SCFAs),as metabolites of intesti-nal flora,have been found to participate in the progression of MASLD.Sodium butyrate(NaB),one of the most important SCFAs,shows therapeutic potentials in MASLD and its mechanisms have not been fully understood.The present study aimed to investigate the effects of NaB on metabolic dysfunction-associated steatohepatitis(MASH)associated fibrosis as well as the underlying mechanisms.Methods:Male Sprague-Dawley rats were randomly assigned to three groups:(i)control group,stan-dard chow for 24 weeks;(ii)HFD group,high-fat and high-cholesterol diet(HFD)for 24 weeks;and(iii)HFD+NaB group,HFD for 24 weeks and NaB gavage for the last 16 weeks.Body weight,liver index(liver weight/body weight×100%),serum parameters,and liver histology were analyzed to evaluate MASH and fibrosis severity.AML12,RAW264.7 and LX2 cell lines were used for in vitro study.Results:Compared to MASH rats with fibrosis induced by 24-week HFD,NaB intervention alleviated the degree of hepatic steatosis,inflammation,hepatocyte ballooning,and fibrosis.Further mechanistic study showed that NaB supplementation significantly decreased miR-155-5p level in the liver and the serum of MASH rats,and the inhibition effects of miR-155-5p on suppressor of cytokine signaling 1(SOCS1)in both hepatocytes and hepatic stellate cells(HSCs)were blunted when they were treated with NaB.Fur-thermore,NaB also significantly decreased the production of platelet-derived growth factor-BB(PDGF-BB),a pro-fibrotic mediator,in hepatocytes.NaB treatment on AML12 cells markedly impaired the prolifera-tion ability of co-cultured LX2 cells.Moreover,NaB intervention or miR-155-5p mimics also interferes extracellular regulated protein kinases signaling in LX2 cells.Conclusions:NaB intervention inhibited HSCs activation via miR-155-5p/SOCS1/PDGF signaling pathway and consequently relieved fibrosis in MASH rats.NaB might be a potential agent for the treatment of fibrosis in patients with MASH.
