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Journal of Lipid Research, Vol. 48, 904-913, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Model-based compartmental analysis indicates a reduced mobilization of hepatic vitamin A during inflammation in rats¹

Sin H. Gieng^*, Michael H. Green, Joanne B. Green and Francisco J. Rosales^2,

^* Children's Hospital Oakland Research Institute, Oakland, CA
Department of Nutritional Sciences, Pennsylvania State University, University Park, PA
Mead Johnson Nutritionals, Evansville, IN

¹ Part of this work was presented at the Federation of American Societies for Experimental Biology 2005, Washington, DC, by S.H.G.

Published, JLR Papers in Press, January 18, 2007.

² To whom correspondence should be addressed. e-mail: francisco.rosales{at}bms.com

Vitamin A (VA) kinetics was studied in rats with marginal VA stores before, during, and after inflammation. Rats received orally [11,12-³H(N)]retinol ([³H]VA; day 0), and inflammation was induced on day 21 with lipopolysacchride (LPS) for 3 days (n = 5) or recombinant human interleukin-6 (rhIL-6) for 7 days (n = 5). Both the fraction of [³H]VA and retinol concentrations in plasma were reduced significantly by LPS or rhIL-6. Compartmental analysis using the Windows version of Simulation, Analysis, and Modeling software was applied to group mean data, and non-steady-state models were developed. After absorption, VA kinetics was described by a three-compartment model that included plasma, kidney/interstitium, and liver/carcass. Four mechanisms decreasing plasma retinol were investigated: increased urinary excretion, increased irreversible loss, increased movement into interstitium, and decreased hepatic mobilization. Modeling demonstrated that a 79% reduction in hepatic mobilization of retinol (from 4.3 to 0.9 nmol/h) by 15 h after LPS best accounted for the observed changes in plasma VA kinetics (sum of squares = 9.05 x 10^–07). rhIL-6 caused an earlier reduction (75% by 5.6 h). These models predicted a return to control values by 10 days after inflammation. If prolonged, inflammation-induced hyporetinolemia can render hepatic retinol unavailable to extrahepatic tissues, possibly leading to their impaired function, as observed in VA-deficient children with measles infection.

Supplementary key words hyporetinolemia • kinetic analysis • retinol • Windows version of Simulation, Analysis, and Modeling software

Abbreviations: AIC, Akaike's Information Criterion; fdose, fraction of the oral dose; IL-6, interleukin-6; LPS, lipopolysaccharide; RBP, retinol binding protein; rhIL-6, recombinant human interleukin-6; TMMP, trimethylmethoxyphenyl; VA, vitamin A; [³H]VA, [11,12-³H(N)]retinol; WinSAAM, Windows version of Simulation, Analysis, and Modeling software

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