Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with lovastatin.

Abstract

L ovastatin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-limiting enzyme in cholesterol biosynthesis.1 The hypocholesterolemic effects of lovastatin in patients with primary hypercholesterolemia have been well established, 2 -10 but the extent to which this drug affects cellular cholesterol homeostasis in humans is less well delineated. Previous in vivo studies in animals and in vitro studies in cells grown in tissue culture have shown that the administration of either lovastatin or a related drug, mevastatin (compactin), results in compensatory increases in the mass of HMG CoA reductase and in the high affinity receptor-mediated degradation of 125 l-low density lipoprotein (LDL) 11 -14 ; the question of whether or not clinically effective doses of lovastatin will induce similar changes in tissues or cells isolated from hypercholesterolemic patients on chronic therapy with lovastatin has, however, not been previously examined. Kinetic studies Received May 13,1988; revision accepted December 23,1988. with radiolabeted LDL have indicated that the hypocholesterolemic effects of lovastatin in patients with heterozygous familial hypercholesterolemia result from both an increased rate of LDL catabolism and a concurrent reduction in the rate of synthesis of LDL 3 The former is believed to be due to an increased number of high affinity LDL receptors expressed on cell membranes, particularly those in the liver.Previous studies have indteated that freshly isolated human mononuctear leukocytes show changes in cholesterol homeostasis that parallel those known to occur in the liver. 16 -18 For example, the rates of cholesterol synthesis and high affinity receptor-mediated degradation of I 12S -LDL in freshly isolated mononuctear leukocytes from patients with heterozygous familial hypercholesterolemia (FH) were both increased during therapy with the bile acid sequestrant colestipol.15 Similarty, dietary cholesterol has been shown to depress cholesterol synthesis or HMG CoA reductase activity in freshly isolated mononuclear leukocytes.1718 Both of these effects parallel those that are known to occur in the liver.In the present study, we utilized freshly isolated mononuclear leukocytes to examine whether therapy with lovastatin influences cholesterol homeostasis in patients with heterozygous FH treated with increasing doses of lovastatin. Methods SubjectsThe 23 adult patients who participated in this study were diagnosed as having heterozygous FH on the basis of persistent primary hypercholesterolemia greater than 355 by guest on May 12, 2018 http://atvb.ahajournals.org/ Downloaded from

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“…In those studies statins increased the expression of numerous cholesterol synthesis-related genes. This is in accordance with the results of Gerber et al [16], Hagemenas and Illingworth [17] and ours [18] proving that inhibition of HMGR activity by statin treatment stimulates an adaptive response in the cell in order to maintain sterol homeostasis, including up-regulation of genes involved in cholesterol biosynthesis, a compensatory increase in HMGR level and consequent partial reduction of the sterol lowering effect.…”

Determinants of Variable Response to Statin Treatment in Patients With Refractory Familial Hypercholesterolemia

“…Alternatively, the lack of significant change in HMG CoA reductase mRNA in the mononuclear leukocytes could reflect the extent to which atorvastatin is sequestered by the liver, resulting in the absence of any inhibitory activity in plasma on the morning after the dose of the previous night, as documented for lovastatin. 36 Thus, plasma MVA seems to be a better index of changes in hepatic cholesterol synthesis during lipid-lowering drug therapy than is leukocyte HMG CoA reductase mRNA, at least in FH patients.…”

Modifying egg yolk cholesterol in the domestic fowl—a review

“…It would be of interest to examine the effects of feeding other agents which inhibit HMG-CoA reductase activity in a manner independent of substrate inhibition, such as the hypolipidemic drug, mevinolin (lovastatin). Mevinolin competitively inhibits HMG-CoA reductase activity and enhances lipoprotein (the tranport mechanisms for cholesterol) turnover (Hagemenas et al, 1986).…”