A pharmacodynamic model of triglyceride transport and deposition during feed deprivation or following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat.
A simplified model of fat metabolism was developed to predict fat synthesis, transport, deposition, and metabolism as a function of feed consumption, as a means of testing mechanisms proposed for the disruption in fat metabolism caused by TCDD. Rates of triglyceride (TG) synthesis and lipolysis were made directly dependent on daily average levels of feed consumption, which could be constant or follow other patterns. Seven compartments, including plasma very low density lipoprotein (VLDL) (1), plasma free fatty acid (FFA) (2), plasma VLDL remnants (3), lipoprotein lipase (LPL)-VLDL complex (4), liver TG (5), white adipose tissue (WAT) TG (6), and brown adipose tissue (BAT) TG (7) were required to obtain realistic rates of TG deposition in storage fat while maintaining normal levels of plasma TGs and FFA. The steady-state level of hepatic TG was very sensitive to the rate of storage fat lipolysis and hepatic VLDL export. Because plasma TG is taken up very rapidly by extra-hepatic tissues, reduction of WAT uptake rates had a greater effect on plasma TG than increasing rates of hepatic synthesis and VLDL export. Our results indicate that neither increased hepatic VLDL synthesis nor a simple inhibition of WAT LPL can, by themselves, explain the combined occurrence of hyperlipidemia and loss of fat observed in TCDD-treated animals. However, a TCDD-mediated enhancement of WAT TG lipolysis and consequential physiological responses in liver and BAT yield results compatible with experimental data.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417.
W L
WL
Roth
L W
LW
Weber
B U
BU
Stahl
K
K
Rozman
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D000072317:Polychlorinated Dibenzodioxins / Q000493:pharmacokinetics*; D051381:Rats; D014280:Triglycerides / Q000378:metabolism / Q000493:pharmacokinetics*
D005227:Fatty Acids; D000072317:Polychlorinated Dibenzodioxins; D014280:Triglycerides