LAUSR

Introduction Nonalcoholic steatohepatitis (NASH) afflicts 20–36% of individuals with nonalcoholic fatty liver disease (NAFLD). A lipotoxic hepatic environment, altered innate immune signaling and inflammation are defining features of progression to NASH. Activated resident liver macrophages express folate receptor beta (FR‐&bgr;) which may be an indicator of progression from steatosis to NASH. The goals of this study were to characterize FR‐&bgr; protein expression in human NAFLD and rodent models of NASH, and demonstrate liver targeting of an FR‐&bgr; imaging agent to the liver of a rodent NASH model using FR‐&bgr;. Methods Rat liver lysates from methionine choline deficient (MCD) fed rats, high fat diet (HFD) and methionine choline sufficient (MC+) rat controls were analyzed for hepatic FR‐&bgr; protein. The FR‐&bgr;‐targeted agent, Etarfolatide was injected into MCD and MC + ‐fed C57BL/6 mice for efficient FastSPECT hepatic imaging. Additionally, FR‐&bgr; expression across the stages of human NAFLD from normal to NASH was assessed. Results FastSPECT images show targeting of Etarfolatide to the liver of mice fed 8 weeks of MCD diet but not control‐fed mice. The MCD rat model exhibited significantly increased protein expression of hepatic FR‐&bgr; in contrast to HFD or normal samples. Similarly human liver samples categorized as NASH Fatty or NASH Not Fatty showed elevated FR‐&bgr; protein when compared to normal liver. FR‐&bgr; transcript expression levels were elevated across both NASH Fatty and NASH Not Fatty samples. Conclusion The findings in this study indicate that FR‐&bgr; expression in NASH may be harnessed to target agents directly to the liver. HighlightsInflammation in NASH is associated with macrophage activation.Etarfolatide, a folate‐linked imaging agent is targeted to activated macrophages.Targeting of Etarfolatide to the liver occurs in mice with MCD diet‐induced NASH.Etarfolatide targeting to the liver does not occur in control mice fed an MC+ diet.FR‐&bgr; protein and mRNA expression are increased in human NASH.