Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis

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-beta) which may be an indicator of progression from steatosis to NASH. The goals of this study were to characterize FR-beta protein expression in human NAFLD and rodent models of NASH, and demonstrate liver targeting of an FR-beta imaging agent to the liver of a rodent NASH model using FR-beta. 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-beta protein. The FR-beta-targeted agent, Etarfolatide was injected into MCD and MC + -fed C57BL/6 mice for efficient FastSPECT hepatic imaging. Additionally, FR-beta 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-beta in contrast to HFD or normal samples. Similarly human liver samples categorized as NASH Fatty or NASH Not Fatty showed elevated FR-beta protein when compared to normal liver. FR-beta transcript expression levels were elevated across both NASH Fatty and NASH Not Fatty samples. Conclusion: The findings in this study indicate that FR-beta expression in NASH may be harnessed to target agents directly to the liver.