摘要
Background and Aims:Metabolic dysfunction-associated steatotic liver disease(MASLD),is the most common form of chronic liver disease worldwide.This study aimed to explore the role of TM6SF2 in high-fat diet(HFD)-induced MASLD through the gut-liver axis.Methods:The TM6SF2 gut-specific knockout(TM6SF2 GKO)mouse was constructed using CRISPR/Cas9 technology.TM6SF2 GKO and wild-type(CON)mice were fed either a HFD or a control diet for 16 weeks to induce MASLD.Blood,liver,and intestinal lipid content,as well as gut microbiota and serum metabolites,were then analyzed.Results:TM6SF2 GKO mice fed an HFD showed elevated liver and intestinal lipid deposition compared to CON mice.The gut microbiota of HFD-fed TM6SF2 GKO mice exhibited a decreased Firmicutes/Bacteroidetes ratio compared to HFD-fed CON mice.The HFD also reduced the diversity and abundance of the microbiota and altered its composition.Aspartate aminotransferase,alanineaminotransferase,and total cholesterol levels were higher in HFD-fed TM6SF2 GKO mice compared to CON mice,while triglyceride levels were lower.Serum metabolite analysis revealed that HFDfed TM6SF2 GKO mice had an increase in the expression of 17 metabolites(e.g.,LPC[18:0/0-0])and a decrease in 22 metabolites(e.g.,benzene sulfate).The differential metabolites of LPC(18:0/0-0)may serve as HFD-fed TM6SF2 serum biomarkers,leading to MASLD exacerbation in GKO mice.Conclusions:TM6SF2 GKO aggravates liver lipid accumulation and liver injury in MASLD mice.TM6SF2 may play an important role in regulating intestinal flora and the progression of MASLD through the gut-liver axis.
基金
funded by The National Natural Science Foundation of China(NSFC,No.82100618)
the China Postdoctoral Science Foundation(No.2021M701820).
