Title

Guinea pigs as models for experimental drugs affecting triglyceride metabolism

Date of Completion

January 2006

Keywords

Biology, Animal Physiology|Health Sciences, Nutrition

Degree

Ph.D.

Abstract

The purpose of this study was to evaluate guinea pigs as models for triglyceride (TG) metabolism by assessing treatment with a microsomal transfer protein (MTP) inhibitor, a hypolipidemic drug and with rapamycin, a drug prescribed to organ transplant patients, which is known to develop hypertriglyceridemia. ^ Partial inhibition of MTP has been documented to decrease circulating lipid levels leading to fatty liver. JTT-130, an MTP inhibitor targeted towards the intestine, was evaluated. Guinea pigs (10/group) were allocated to a control (no drug) low dose or high dose of JTT-130 for 4 wk following a 3 wk-treatment with a hypercholesterolemic diet. JTT-130 significantly reduced plasma total cholesterol (TC) by 20%, and TG by 30% concentrations compared to controls without causing fatty liver. The activity of hepatic regulatory enzymes of cholesterol synthesis, esterification and catabolism were not affected by drug treatment. These data suggest that JTT-130 has the potential to be used as a lipid-lowering drug in clinical settings. ^ In a second study guinea pigs (10/group) were treated with 0, low or high dose of rapamycin (RAPA) to trace the pathways leading to hyperlipidemia. Increases in plasma TG by 50% without affecting plasma TC values was observed after 3-wk treatment. Plasma glucose (+ 57%), free fatty acids (FFA) (+ 65%), aortic TG (+ 41.7%) and TNF-α (+ 945%) were increased (P < 0.01) in high PAPA groups. Results suggest that RAPA affects VLDL secretion and promotes aortic deposition of TG. Because low-RAPA decreased TC accumulation in liver and aorta and had less of an effect on plasma FFA and aortic TNF-α compared to high-RAPA (P < 0.01), low RAPA treatment could be less detrimental to organ transplant individuals. ^ A third objective of this dissertation was to evaluate the relationship between liver and mononuclear cell's gene expression for target proteins regulating hepatic cholesterol metabolism. RT-PCR, results from HMG-CoA reductase and LDL receptor expression demonstrated a positive correlation between liver and mononuclear cells. These results suggest that mononuclear cells have the potential to be used as an index for liver metabolism to assess diet and drug effects on the expression of these ubiquitously distributed proteins. ^