Interactions of dietary phytosterols with lipid-lowering drugs in apolipoprotein E deficient mice

Phytosterols are chemicals naturally found in vegetable oils, seeds, nuts, and some tree products.lt has been shown that plant sterols inhibit cholesterol absorption, thereby lowering plasma total and low-density lipoprotein (LDL) cholesterol levels without significanfly altering high-density lipoprotein (HDL) chotesterol or triglycerides (TG).cholesterol-lowering effects of phytosterols are associated with a significant reduction in atherosclerosis in apo E_ knokout (apo E_KO) mice.Monotherapy with either níacin or fibrates is an effective strategy in patients with predominantly elevated rG and low HDl-cholesterol levels.However, a combination drug therapy is necessary in patients who do not adequately respond to single therapy or in patients with mixed dyslipidemia (increased LDl-cholesterol and rG levels plus reduced HDl-cholesterol concentrations)' severat clinical trials have studied the combination of statins plus niacin or fíbrate in patients with mixed dysrypidemia.However, safety, tolerabirity and cost are major rimiting factors in drug combination therapy.It is weil known that phytosterors reduce prasma totar and LDL cholesterol concentrations with no significant effect on HDl-cholesterol or TG levels.on the other hand, niacin and fenofibrate increase prasma HDL_ cholesterol levels and decrease TG concentrations.Therefore a combination of phytosterols with niacin or fenofibrate may reduce both plasma cholesterol and rG concentratíons as well as increase HDl-cholesterol levels, resulting in a more anti-atherogenic ripoprotein profire as compared to singre therapy.ilt The interactions between phytosterols and non-statin lipid-lowering agents have not been studied.Thus, it was hypothesized that a combination of phytosterols with niacin or fenofibrate will synergistically impact lípoprotein profile and atherogenesis in apolipoprotein E deficient (apo E-Ko) mice.Male apo E-KO mice were fed a cholesterol-enriched diet supplemented with phytosterols (2o/o wlw, n=g), fenofibrate (0.1 o/o wlw, n=g), niacin (0.5% w/w, n=8) or a combination of 2% of the phytosterol mixture with either fenofibrate (0.1o/o w/w, n=g) or niacin (o.s% Mw, n=g) for 12 weeks.Body weights were recorded weekly and plasma lipid profiles were determined at four-week intervals.The hearts and aortas were collected and fixed for histological and morphometrical evaluations of atherosclerotic lesions.Phytosterols alone significantly reduced plasma total cholesterol levels (11 .7 vs 17.0 mmol/L, p<0.05) and the extent of atherosclerosis (0.15 vs 0.42 mm2, p<0.05).ln contrast, fenofibrate paradoxically increased total cholesterol and rG by 6s% and lovo, respectivery, and decreased HDL- cholesterol levels by 40% without significant changes on atherosclerosis as compared to controls.The addition of fenofibrate to phytosterols increased plasma total cholesteror revels by 40% (20.0 vs 14.1 mmol/L, pco.0s) and decreased HDl-cholesteror cóncentrations by 50% (0.4 vs 0.g mmol/L).These changes were accompanied by slight reductíons in the extent of atherosclerosis (0.34 vs 0.42 mmz' p>0.05) as compared to controls.Niacin alone had no significant effect on atherosclrotic lesions, and failed to decrease TG or to increase HDl-cholesterol levels.However, a combination IV of niacin with phytosterols caused an increase of 1s0o/o (p<0.05) in HDL_ cholesterol concentrations and a decrease of 22o/o (p<0.05) in totar cholesterol levels which were associated with significant reductions (6s%, p<0'05) in atherosclerotic lesion size as compared to controls.The results therefore suggest that: First, addition of plant sterols to niacin may beneficially alter plasma lipoprotein profile and consequenfly affect atherogenesis in apo E-Ko míce' Second, addition of phytosterols to fenofibrate did not result in reductions in plasma cholesterol level and atherosclerotic lesion size in apo E-Ko mice' Thirth, a combination of phytosterols plus fenofibrate or niacin do not appear to change the morphotogy of the liver and kidney tissues.V ACKNOWLWDGEMENTS I am deepry gratefur to my supervisor Dr. Mohammed Moghadasian for his patience and encouragement that carried me on through difficult times, and for his insights and suggestions that helped to shape my research skills.

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