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J Clin Invest. 1987 December; 80(6): 1692–1697.
PMCID: PMC442441

Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein B synthesis.


Cholesteryl ester storage disease (CESD) is characterized by the deficient activity of lysosomal cholesteryl ester (CE) hydrolase, accumulation of LDL-derived CE in lysosomes, and hyperlipidemia. We studied the kinetics of VLDL and LDL apolipoprotein B (apoB), using 125I-VLDL and 131I-LDL, in a 9-yr-old female with CESD and elevated total cholesterol (TC) (271.0 +/- 4.4 mg/dl), triglyceride (TG) (150.0 +/- 7.8 mg/dl), and LDL cholesterol (184.7 +/- 3.4 mg/dl). These studies demonstrated a markedly elevated production rate (PR) of apoB, primarily in LDL, with normal fractional catabolism of apoB in VLDL and LDL. Urine mevalonate levels were elevated, indicative of increased synthesis of endogenous cholesterol. Treatment with lovastatin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, resulted in significant reductions in TC (196.8 +/- 7.9 mg/dl), TG (100.8 +/- 20.6 mg/dl), and LDL cholesterol (102.0 +/- 10.9 mg/dl). Therapy reduced VLDL apoB PR (5.2 vs. 12.2 mg/kg per d pretreatment) and LDL apoB PR (12.7 vs. 24.2 mg/kg per d pretreatment). Urine mevalonate levels also decreased during therapy. These results indicate that, in CESD, the inability to release free cholesterol from lysosomal CE resulted in elevated synthesis of endogenous cholesterol and increased production of apoB-containing lipoproteins. Lovastatin reduced both the rate of cholesterol synthesis and the secretion of apoB-containing lipoproteins.

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  • ABRAMOV A, SCHORR S, WOLMAN M. Generalized xanthomatosis with calcified adrenals. AMA J Dis Child. 1956 Mar;91(3):282–286. [PubMed]
  • Kelly DR, Hoeg JM, Demosky SJ, Jr, Brewer HB., Jr Characterization of plasma lipids and lipoproteins in cholesteryl ester storage disease. Biochem Med. 1985 Feb;33(1):29–37. [PubMed]
  • Kostner GM, Hadorn B, Roscher A, Zechner R. Plasma lipids and lipoproteins of a patient with cholesteryl ester storage disease. J Inherit Metab Dis. 1985;8(1):9–12. [PubMed]
  • Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3957–3961. [PubMed]
  • Melish J, Le NA, Ginsberg H, Steinberg D, Brown WV. Dissociation of apoprotein B and triglyceride production in very-low-density lipoproteins. Am J Physiol. 1980 Nov;239(5):E354–E362. [PubMed]
  • Le NA, Melish JS, Roach BC, Ginsberg HN, Brown WV. Direct measurement of apoprotein B specific activity in 125I-labeled lipoproteins. J Lipid Res. 1978 Jul;19(5):578–584. [PubMed]
  • Gibson JC, Rubinstein A, Bukberg PR, Brown WV. Apolipoprotein E-enriched lipoprotein subclasses in normolipidemic subjects. J Lipid Res. 1983 Jul;24(7):886–898. [PubMed]
  • Ginsberg HN, Le NA, Gibson JC. Regulation of the production and catabolism of plasma low density lipoproteins in hypertriglyceridemic subjects. Effect of weight loss. J Clin Invest. 1985 Feb;75(2):614–623. [PMC free article] [PubMed]
  • Ramakrishnan R, Dell RB, Goodman DS. On determining the extent of side-pool synthesis in a three-pool model for whole body cholesterol kinetics. J Lipid Res. 1981 Nov;22(8):1174–1180. [PMC free article] [PubMed]
  • Parker TS, McNamara DJ, Brown CD, Kolb R, Ahrens EH, Jr, Alberts AW, Tobert J, Chen J, De Schepper PJ. Plasma mevalonate as a measure of cholesterol synthesis in man. J Clin Invest. 1984 Sep;74(3):795–804. [PMC free article] [PubMed]
  • Heiss G, Tamir I, Davis CE, Tyroler HA, Rifkand BM, Schonfeld G, Jacobs D, Frantz ID., Jr Lipoprotein-cholesterol distributions in selected North American populations: the lipid research clinics program prevalence study. Circulation. 1980 Feb;61(2):302–315. [PubMed]
  • Goldstein JL, Dana SE, Faust JR, Beaudet AL, Brown MS. Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease. J Biol Chem. 1975 Nov 10;250(21):8487–8495. [PubMed]
  • Janus ED, Nicoll AM, Turner PR, Magill P, Lewis B. Kinetic bases of the primary hyperlipidaemias: studies of apolipoprotein B turnover in genetically defined subjects. Eur J Clin Invest. 1980 Apr;10(2 Pt 1):161–172. [PubMed]
  • Langer T, Strober W, Levy RI. The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia. J Clin Invest. 1972 Jun;51(6):1528–1536. [PMC free article] [PubMed]
  • Simons LA, Reichl D, Myant NB, Mancini M. The metabolism of the apoprotein of plasma low density lipoprotein in familial hyperbetalipoproteinaemia in the homozygous form. Atherosclerosis. 1975 Mar-Apr;21(2):283–298. [PubMed]
  • Bilheimer DW, Goldstein JL, Grundy SM, Brown MS. Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia. J Clin Invest. 1975 Dec;56(6):1420–1430. [PMC free article] [PubMed]
  • Soutar AK, Myant NB, Thompson GR. Simultaneous measurement of apolipoprotein B turnover in very-low-and low-density lipoproteins in familial hypercholesterolaemia. Atherosclerosis. 1977 Nov;28(3):247–256. [PubMed]
  • Beltz WF, Kesäniemi YA, Howard BV, Grundy SM. Development of an integrated model for analysis of the kinetics of apolipoprotein B in plasma very low density lipoproteins, intermediate density lipoproteins, and low density lipoproteins. J Clin Invest. 1985 Aug;76(2):575–585. [PMC free article] [PubMed]
  • Kovanen PT, Bilheimer DW, Goldstein JL, Jaramillo JJ, Brown MS. Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1194–1198. [PubMed]
  • La Ville A, Moshy R, Turner PR, Miller NE, Lewis B. Inhibition of cholesterol synthesis reduces low-density-lipoprotein apoprotein B production without decreasing very-low-density-lipoprotein apoprotein B synthesis in rabbits. Biochem J. 1984 Apr 1;219(1):321–323. [PubMed]
  • Huff MW, Telford DE, Woodcroft K, Strong WL. Mevinolin and cholestyramine inhibit the direct synthesis of low density lipoprotein apolipoprotein B in miniature pigs. J Lipid Res. 1985 Oct;26(10):1175–1186. [PubMed]
  • Grundy SM, Vega GL. Influence of mevinolin on metabolism of low density lipoproteins in primary moderate hypercholesterolemia. J Lipid Res. 1985 Dec;26(12):1464–1475. [PubMed]
  • Ruderman NB, Jones AL, Krauss RM, Shafrir E. A biochemical and morphologic study of very low density lipoproteins in carbohydrate-induced hypertriglyceridemia. J Clin Invest. 1971 Jun;50(6):1355–1368. [PMC free article] [PubMed]
  • Angelin B, Einarsson K, Hellström K, Leijd B. Effects of cholestyramine and chenodeoxycholic acid on the metabolism of endogenous triglyceride in hyperlipoproteinemia. J Lipid Res. 1978 Nov;19(8):1017–1024. [PubMed]

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