RT Journal Article
SR Electronic
T1 Assessing Steatotic Liver Function after Ischemia-Reperfusion Injury by In Vivo Multiphoton Imaging of Fluorescein Disposition
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 154
OP 162
DO 10.1124/dmd.114.060848
VO 43
IS 1
A1 Camilla A. Thorling
A1 Lu Jin
A1 Michael Weiss
A1 Darrell Crawford
A1 Xin Liu
A1 Frank J. Burczynski
A1 David Liu
A1 Haolu Wang
A1 Michael S. Roberts
YR 2015
UL http://dmd.aspetjournals.org/content/43/1/154.abstract
AB Ischemia-reperfusion injury, a common complication during liver surgery where steatotic livers are more prone to the injury, may become more prevalent in the growing obese population. This study characterizes liver morphology toward understanding changes in subcellular function in steatotic livers exposed to ischemia-reperfusion injury through quantitative description of fluorescein distribution obtained by minimally invasive in vivo multiphoton microscopy using a physiologic pharmacokinetic model. Rats were fed a high-fat diet for 7 days to induce liver steatosis. Partial ischemia was induced after reperfusion for 4 hours, when fluorescein (10 mg/kg) was injected intravenously. Liver images, bile, and blood were collected up to 180 minutes after injection. Ischemia-reperfusion injury was associated with an increase in alanine transaminase levels and apoptosis. In addition, steatosis featured lipid droplets and an increase in fluorescein-associated fluorescence observed in hepatocytes via multiphoton imaging. Analysis of the hepatic concentration-time profiles has suggested that the steatosis-induced increase in fluorescein-associated fluorescence mainly arises by inducing hepatic fluorescein metabolism. The combination of ischemia-reperfusion with steatosis exacerbates these effects further. This was confirmed by fluorescence lifetime imaging microscopy showing a decreased average fluorescence lifetime of the liver, which is indicative of an increased production of the metabolite. Our results show the potential of noninvasive dye imaging for improving our understanding of liver disease induced by subcellular changes in vivo, providing further quantitative measures of metabolic and biliary liver function, and hence extending the qualitative liver function tests now available.