title: Regulation of cholesterol biosynthesis in sitosterolemia: effects of lovastatin, cholestyramine, and dietary sterol restriction.
abstract: We investigated the effects of lovastatin, cholestyramine, and dietary sterol restriction on cholesterol synthesis and low density lipoprotein receptor function in freshly isolated mononuclear leukocytes from two unrelated sitosterolemic families. Total plasma sterol concentrations were elevated in the two homozygous sitosterolemic subjects (343 and 301 vs. 185 mg/dl in controls) and contained increased amounts of plant sterols and 5 alpha-saturated stanols (20% and 8% vs. less than 1% in controls), but were not significantly different from controls in the two heterozygous subjects. The rates of conversion of acetate to cholesterol by mononuclear leukocytes were subnormal in all homozygous and heterozygous subjects and correlated with markedly reduced microsomal 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase activity. In the two homozygous subjects, cholestyramine treatment decreased plasma sterols 29% and 35%, and yet was associated with a paradoxical decline in mononuclear leukocyte HMG-CoA reductase activity. In contrast, plasma sterol concentrations decreased 14% and 5%, and mononuclear leukocyte HMG-CoA reductase activities increased 13% and 46% in three control and one heterozygous subjects treated with cholestyramine, respectively. Plasma sterol concentrations in the homozygous subjects unexpectedly failed to decline during treatment with lovastatin or a low sterol diet. In distinction, plasma sterol concentrations in three control and one heterozygous subjects dropped 28% and 31%, respectively, during treatment with lovastatin. Both cholestyramine and low dietary sterols stimulated low density lipoprotein receptor function. These results demonstrate a marked abnormality in cholesterol homeostasis in patients with homozygous sitosterolemia with xanthomatosis.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103.
authors.forename: L B
authors.initials: LB
authors.lastname: Nguyen
authors.forename: M
authors.initials: M
authors.lastname: Cobb
authors.forename: S
authors.initials: S
authors.lastname: Shefer
authors.forename: G
authors.initials: G
authors.lastname: Salen
authors.forename: G C
authors.initials: GC
authors.lastname: Ness
authors.forename: G S
authors.initials: GS
authors.lastname: Tint
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002784:Cholesterol / Q000096:biosynthesis*; D002792:Cholestyramine Resin / Q000494:pharmacology / Q000627:therapeutic use*; D004032:Diet; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008875:Middle Aged; D011973:Receptors, LDL / Q000187:drug effects / Q000502:physiology; D012855:Sitosterols / Q000097:blood*; D013261:Sterols / Q000008:administration & dosage*
chemical_list: D011973:Receptors, LDL; D012855:Sitosterols; D013261:Sterols; D002792:Cholestyramine Resin; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases