摘要
Metabolic dysfunction-associated steatohepatitis(MASH),a severe type of metabolic dysfunction-associated steatotic liver disease(MASLD),is a leading etiology of end-stage liver disease worldwide,posing significant health and economic burdens.microRNA-320(miR-320),a ubiquitously expressed and evolutionarily conserved miRNA,has been reported to regulate lipid metabolism;however,whether and how miR-320 affects MASH development remains unclear.By performing miR-320 in situ hybridization with RNAscope,we observed a notable downregulation of miR-320 in hepatocytes during MASH,correlating with disease severity.Most importantly,miR-320 downregulation in hepatocytes exacerbated MASH progression as demonstrated that hepatocyte-specific miR-320 deficient mice were more susceptible to high-fat,high-fructose,high-cholesterol diet(HFHC)or choline-deficient,amino acid-defined,high-fat diet(CDAHFD)-induced MASH compared with control littermates.Conversely,restoration of miR-320 in hepatocytes ameliorated MASH-related steatosis and fibrosis by injection of adeno-associated virus 8(AAV8)carrying miR-320 in different types of diet-induced MASH models.Mechanistic studies revealed that miR-320 specifically regulated fibroblast growth factor 1(FGF1)production in hepatocytes by inhibiting regulator factor X1(RFX1)expression.Notably,knockdown of Rfx1in hepatocytes mitigated MASH by enhancing FGF1-mediated AMPK activation.Our findings underscore the therapeutic potential of hepatic miR-320 supplementation in MASH treatment by inhibiting RFX1-mediated FGF1 suppression.
基金
supported by the National Natural Science Foundation of China(82300657 and 82270601)
the National Key Research and Development Program of China(2023YFA1800804)
the Natural Science Foundation of Shanghai(22ZR1473800,China).
