TY - JOUR
T1 - Folate receptor-beta expression as a diagnostic target in human & rodent nonalcoholic steatohepatitis
AU - Lake, April D.
AU - Hardwick, Rhiannon N.
AU - Leamon, Christopher P.
AU - Low, Philip S.
AU - Cherrington, Nathan J.
N1 - Funding Information:
This research was supported by the National Institutes of Health [Grants DK068039 ; ES006694 , ES007091 , AT002842 and HD062489 ]; and the Liver Tissue Cell Distribution System was supported by the National Institutes of Health [Contract N01-DK-7-0004/HHSN267200700004C ].
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - Folate receptor-beta
KW - Imaging
KW - Macrophages
KW - NAFLD
KW - NASH models
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U2 - 10.1016/j.taap.2019.02.009
DO - 10.1016/j.taap.2019.02.009
M3 - Article
C2 - 30794826
AN - SCOPUS:85061893441
VL - 368
SP - 49
EP - 54
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
ER -