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

April D. Lake, Rhiannon N. Hardwick, Christopher P. Leamon, Philip S. Low, Nathan J. Cherrington

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Pages (from-to)49-54
Number of pages6
JournalToxicology and Applied Pharmacology
Volume368
DOIs
StatePublished - Apr 1 2019

Keywords

  • Folate receptor-beta
  • Imaging
  • Macrophages
  • NAFLD
  • NASH models

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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