Conclusions
Hepatocyte EVs are therapeutic in a mouse model of diet-induced steatohepatitis with fibrosis. Further studies of hepatocyte EVs or their cargo components as novel therapeutics for MASH in humans are warranted, including treatment of fibrotic stages, which are associated with clinical demise and are predictive of patient death.
Methods
C57BI/6J mice were fed a choline-deficient amino acid-defined high (60%) fat (CDAA-HF) diet for up to 12 weeks while receiving i.p. administration of EVs purified from cultured human HepG2 hepatocytes.
Results
CDAA-HF diet consumption resulted in severe hepatic steatosis, increased frequency of CD45+ lymphocytes and F4/80+ macrophages, robust production of aortic smooth muscle actin (ACTA2), and deposition of interstitial collagen, as well as altered serum levels of ALT, AST, cholesterol, triglycerides, alkaline phosphatase, unconjugated bilirubin, and total protein, thus recapitulating typical MASH phenotypes. EVs administered preventively or therapeutically resulted in the restoration of serum marker levels, reduced hepatic inflammation and attenuation of collagen deposition, ACTA2 production, and expression of fibrosis-associated genes. HepG2 EVs contained 205 miRs and, among the 30 most abundant miRs, seven (miRs-423-5p, -483-5p, -191-5p, -148a-3p, -423-3p, -92a-3p, -122-5p) are predicted to directly target fibrosis-related genes (collagens, ACTA2, MMPs, and TIMPs). Conclusions: Hepatocyte EVs are therapeutic in a mouse model of diet-induced steatohepatitis with fibrosis. Further studies of hepatocyte EVs or their cargo components as novel therapeutics for MASH in humans are warranted, including treatment of fibrotic stages, which are associated with clinical demise and are predictive of patient death.