Effects of hypolipidemic drugs on the expression of genes involved in high density lipoprotein metabolism in the rat.
Since plasma high density lipoprotein (HDL) concentrations are inversely related to the development of atherosclerosis, induction of HDL after pharmacological treatment is considered of benefit. To study whether currently used hypolipidemic drugs affect HDL metabolism by modulating the expression of genes involved in HDL metabolism, liver and intestinal apolipoprotein (apo) AI, apo-AII and apo-AIV gene expression was evaluated in rats treated with different classes of hypolipidemic drugs, and correlated to the changes in plasma lipid and apolipoprotein concentrations. In rats, the most pronounced hypolipidemic effects were observed after treatment with the fibrates clofibrate and fenofibrate, which lowered plasma lipid, apo-AI and apo-AIV concentrations. This decrease was accompanied by lowered liver apo-AI, apo-AII and apo-AIV mRNA levels. None of the other compounds tested affected plasma cholesterol, whereas probucol and simvastatin decreased plasma triglyceride concentrations. Apo-AI and apo-AII mRNA remained constant after nicotinic acid and probucol, whereas liver apo-AIV mRNA levels decreased. Cholestyramine increased hepatic apo-AI and apo-AII, but not apo-AIV mRNA levels. Simvastatin treatment increased apo-AI mRNA nearly threefold, whereas apo-AII and apo-AIV decreased by more than 50%. Similarly as after cholestyramine, the alteration in hepatic apo-AI mRNA levels did not result in changed plasma apo-AI concentrations. Remarkably, none of the drugs tested significantly affected intestinal apolipoprotein mRNA levels. These results indicate that hypolipidemic drugs may act on plasma lipoprotein metabolism by regulating apolipoprotein gene expression. Further studies in humans and primates are therefore warranted.
Staels
B
B
U325 INSERM, Department of Atherosclerosis, Pasteur Institute, Lille, France.
Van Tol
A
A
Fruchart
J C
JC
Auwerx
J
J
D000199:Actins / Q000378:metabolism; D000818:Animals; D001053:Apolipoproteins / Q000235:genetics / Q000378:metabolism; D002792:Cholestyramine Resin / Q000494:pharmacology; D002994:Clofibrate / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009525:Niacin / Q000494:pharmacology; D011341:Probucol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin
D000199:Actins; D001053:Apolipoproteins; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D002792:Cholestyramine Resin; D009525:Niacin; D008148:Lovastatin; D019821:Simvastatin; D002994:Clofibrate; D011341:Probucol; D011345:Fenofibrate