3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and hepatic apolipoprotein B secretion

Current Opinion in Lipidology

Volumn 8, Issue 3, 1997, Pages 138-145

  Huff, Murray W ^a   Burnett, John R ^a  

^a ROBARTS RESEARCH INSTITUTE   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

APOLIPOPROTEIN B; ATORVASTATIN; CHOLESTEROL; CHOLESTEROL ACYLTRANSFERASE; ENZYME INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; MEVINOLIN; SIMVASTATIN; VERY LOW DENSITY LIPOPROTEIN;

CELL CULTURE; CHOLESTEROL SYNTHESIS; ENZYME ACTIVITY; HUMAN; LIPOPROTEIN BLOOD LEVEL; LIPOPROTEIN SECRETION; LIPOPROTEIN SYNTHESIS; LIVER CELL; LIVER MICROSOME; NONHUMAN; PRIORITY JOURNAL; PROTEIN ASSEMBLY; REVIEW;

ANIMALS; ANTICHOLESTEREMIC AGENTS; APOLIPOPROTEINS B; ENZYME INHIBITORS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; LIVER; LOVASTATIN; MODELS, BIOLOGICAL; SIMVASTATIN;

ANIMALIA;

EID: 0030859045     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041433-199706000-00003     Document Type: Review

References (74)

1. Chan L: Apolipoprotein B, the major protein component of triglyceride rich and low density lipoprotein. J Biol Chem 1992, 267:25621-25624
2. Sigurdsson GA, Nicholl GA, Lewis B: Conversion of very low density lipoprotein to low density lipoprotein. A metabolic study of apolipoprotein B kinetics in human subjects. J Clin Invest 1975, 56:1481-1490.
3. Brown MS, Goldstein JL: A receptor-mediated pathway for cholesterol homeostasis. Science 1986, 232:34-47.
4. The Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344:1383-1389.
5. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995, 333:1301-1307. This study clearly demonstrated that the HMG-CoA reducase inhibitor, pravastatin, significantly reduced coronary events by 31% in hypercholesterolemic patients without overt coronary heart disease. Pravastatin lowered LDL-cholesterol by 26%.
6. Sacks FM, Pfeffer MA, Lemuel AM, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C et al.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996, 335:1001-1009. The Cholesterol and Recurrent Events trial, as with the Scandinavian Simvastatin Survival Study [4], demonstrated that lowering LDL-cholesterol reduces the risk of coronary heart desease events and revascularization procedures. The new and important finding in the Cholesterol and Recurrent Events trial is that the benefits of pravastatin treatment are manifest in patients with coronary heart disease and lower baseline lipid levels than in previous studies [4].
7. Hampton R, Dimster-Denk D, Rine J: The biology of HMG-CoA reductase: the pros of contra-regulation. TIBS 1996, 21:140-145.
8. Davignon J, Montigny M, Dufour R: HMG-CoA reductase inhibitors: a look back and a look ahead. Can J Cardiol 1992, 8:843-864.
9. Thompson GM, Naoumova RP, Watts GF: Role of cholesterol in regulating apolipoprotein B secretion by the liver. J Lipid Res 1996, 37:439-447. This comprehensive review focuses on recent evidence from studies in cultured cells, animals and humans that cholesterol and cholesteryl ester regulate hepatic apoB secretion.
10. Pease RJ, Leiper JM: Regulation of hepatic apolipoprotein-B-containing lipoprotein secretion. Curr Opin Lipidol 1996, 7:132-138.
11. Cianflone K, Yasruel Z, Rodriguez MA, Vas D, Sniderman AD: Regulation of apoB secretion from HepG2 cells: evidence for a critical role for cholesterol ester synthesis in the response to a fatty acid challenge. J Lipid Res 1990, 31:2045-2055
12. Qin W, Infante J, Wang S, Infante R: Regulation of HMG-CoA reductase, apoprotein-B and LDL receptor gene expression by the hypocholesterolemic drugs simvastatin and ciprofibrate in HepG2, human and rat hepatocytes. Biochim Biophys Acta 1992, 1127:57-66.
13. Benoist F, Grand-Perret T: ApoB-100 secretion by HepG2 cells is regulated by the rate of triglyceride biosynthesis but not by intracellular lipid pools. Arterioscler Thromb Vasc Biol 1996, 16:1229-1235.
14. Wu X, Sakata N, Lui E, Ginsberg HN: Evidence for a lack of regulation of the assembly and secretion of apolipoprotein B-containing lipoprotein from HepG2 cells by cholesteryl ester. J Biol Chem 1994, 269:12375-12382.
15. Gibbons GF, Khurana A, Odwell A, Seelaender MCL: Lipid balance in HepG2 cells: active synthesis and impaired mobilization. J Lipid Res 1994, 35:1801-1808.
16. Wu X, Shang A, Jiang H, Ginsberg HN: Low rates of apoB secretion from HepG2 cells result from reduced delivery of newly synthesized triglyceride to a 'secretion-coupled' pool. J Lipid Res 1996, 37:1198-1206. This paper confirms a previous report [15] that HepG2 cells are defective in mobilization of stored cellular triglyceride for lipoprotein assembly and secretion. These findings suggest that interpretation of studies of the regulation of apoB secretion using this cell line should be made with caution.
17. Bocan TMA, Ferguson E, McNally W, Uhlendorf PD, Mueller SB, DeHart P, Sliskovic DR, Roth BD, Krause BR, Newton RS: Hepatic and nonhepatic sterol synthesis and tissue distribution following administration of liver selective HMG-CoA reductase inhibitor, Cl-981: comparison with selected HMG-CoA reductase inhibitors. Biochim Biophys Acta 1992, 1123:133-144.
18. Macri J, Mohammadi A, Newton HS, Adeli K: Effect of atorvastatin on intracellular translocation and degradation of apolipoprotein B in permeabilized HepG2 cells [Abstract]. XII Internationa/Symposium of Drugs Affecting Lipid Metabolism, Houston, Tx 1995:53.
19. Tanaka M, Jingami H, Otani H, Cho M, Ueda Y, Arai H, Nagano Y, Doi T, Yokoke M, Kita T: Regulation of apolipoprotein B production and secretion in response to the change of intracellular cholesteryl ester content in rabbit hepatocytes. J Biol Chem 1993, 268:12713-12718.
20. Ribeiro A, Mangeney M, Loriette C, Thomas G, Pepin D, Janvier B, Chambaz J, Bereziat G: Effect of simvastatin on the synthesis and secretion of lipoproteins in relation to the metabolism of cholesterol in cultured hepatocytes. Biochim Biophys Acta 1991, 1086:279-286.
21. Khan BV, Wilcox HG, Heimberg M: Cholesterol is required for secretion of very-low-density lipoprotein by rat liver. Biochem J 1989, 259:807-816.
22. Khan BV, Fungwe TV, Wilcox HG, Heimberg M: Cholesterol is required for the secretion of the very-low-density lipoprotein: in vivo studies. Biochim Biophys Acta 1990, 1044:297-304.
23. Kasim SE, Elovson J, Khilnani S, Almario RU, Jen KC: Effect of lovastatin on the secretion of very low density lipoprotein lipids and apolipoprotein B in the hypertriglyceridemic Zucker obese rat. Atherosclerosis 1993, 104:147-152.
24. Krause BR, Newton RS: Lipid-lowering activity of atorvastatin in rodent species: triglyceride-lowering in rats predicts efficacy in LDL animal models. Atherosclerosis 1995, 117:237-244. In endogenous hypercholesterolemic rats (sucrose-fed), atorvastatin and lovastatin at doses of 30 mg per day reduced hepatic triglyceride secretion by 66% and 53%, respectively, as assessed by the Triton WR-1339 technique. Plasma apoB was significantly decreased by atorvastatin (-31%) whereas lovastatin had no effect on plasma apoB. These results are consistent with the concept that one of the mechanisms of reductase inhibitors is inhibition of the hepatic production of apoB-containing lipoproteins.
25. Conde K, Vergara-Jimenez M, Krause BR, Newton RS, Fernandez ML: Hypocholesterolemic actions of atorvastatin are associated with alterations in hepatic cholesterol metabolism and lipoprotein composition in the guinea pig. J Lipid Res 1996, 37:2372-2382. In this important study, guinea pigs were fed a 15% (w/w) diet that is known to increase hepatic secretion of apoB-containing lipoproteins. Treatment with atorvastatin (1 to 20 mg/kg per day) significantly reduced the concentrations plasma apoB by up to 70%. Using the Triton WR-1339 technique, secretion rates of apoB were significantly reduced by up to 76%. Importantly, a reduction in hepatic microsomal cholesterol (-50%) together with a 61% reduction in hepatic microsomal ACAT activity was found. These results suggest that the reduction in ACAT activity may be the result of a decrease in substrate free-cholesterol concentration by atorvastatin.
26. Huff MW, Telford DE, Woodcraft K, Strong WLP: Mevinolin and cholestyramine inhibit the direct synthesis of low density lipoprotein apolipoprotein B in miniature pigs. J Lipid Res 1985, 26:1175-1186.
27. Huff MW, Telford DE: Regulation of low density lipoprotein apoprotein B metabolism by lovastatin and cholestyramine in miniature pigs: effects on LDL composition and synthesis of LDL subfractions. Metabolism 1989, 38:256-264.
28. Auerbach BJ, Krause BR, Bisgaier CL, Newton RS: Comparative effects of HMG-CoA reductase inhibitors on apoB production in the casein-fed rabbit: atorvastatin versus lovastatin. Atherosclerosis 1995, 115:173-180.
29. Shames DM, Havel RJ: De novo production of low density lipoproteins: fact or fancy. J Lipid Res 1991, 32:1099-1112.
30. Burnett JR, Wilcox LJ, Telford DE, Kleinstiver SJ, Barrett PHR, Newton RS, Huff MW: Inhibition of apoB secretion by atorvastatin, in vivo, is correlated with decreased hepatic apoB mRNA abundance [Abstract]. Circulation 1996, 94:1-632
31. Vega GL, Krauss RM, Grundy SM: Pravastatin therapy in primary moderate hypercholesterolemia: changes in metabolism of apolipoprotein B-containing lipoproteins. J Intern Med 1990, 227:81-94.
32. Arad Y, Ramakrishnan R, Ginsberg HN: Lovastatin therapy reduces low density lipoprotein apoB levels in subjects with combined hyperlipidemia by reducing the production of apoB-containing lipoproteins: implications for the pathophysiology of apoB production. J Lipid Res 1990, 30:567-582.
33. Arad Y, Ramakrishnan R, Ginsberg HN: Effects of lovastatin therapy on very-low-density lipoprotein triglyceride metabolism in subjects with combined hyperlipidemia: evidence for reduced assembly and secretion of triglyceride-rich lipoproteins. Metabolism 1992, 41:487-493.
34. Gaw A, Packard CJ, Murray EF, Lindsay GM, Griffin BA, Caslake MJ, Vallance BD, Lorimer AR, Shepherd J: Effects of simvastatin on apoB metabolism and LDL subfraction distribution. Arterioscler Thromb 1993, 13:170-189.
35. Gaw A, Lindsay GM, Murray EF, Griffin BA, Caslake MJ, Colquhoun I, Wheatley DJ, Lorimer AR, Shepherd J: Effects of colestipol alone and in combination with simvastatin on apolipoprotein B metabolism. Arterioscler Thromb Vasc Biol 1996, 16:236-249. In eight patients with coronary heart disease and primary moderate hypercholesterolemia, apoB metabolism was assessed using the dual-label VLDL subfraction turnover method, during treatment with colestipol alone and in combination with simvastatin. The principal findings were that, compared with baseline, colestipol plus simvastatin significantly decreased plasma LDL-apoB owing to a significant reduction in LDL-apoB production. LDL-apoB direct synthesis was reduced whereas LDL-apoB derived from VLDL and IDL was not changed. No effect on VLDL- or IDL-apoB production was observed; however, the IDL fractional removal rate for direct catabolism was significantly increased by the combination treatment.
36. Cummings MH, Watts GF, Umpleby M, Hennessy TR, Quiney JR, Sönksen PH: Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolemia: a stable isotope study. Atherosclerosis 1995, 113:79-89
37. Watts GF, Cummings MH, Umpleby M, Quiney JR, Naoumova R, Thompson GR, Sönksen PH: Simvastatin decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: pathophysiological and therapeutic implications. Eur J Clin Invest 1995, 25:559-567. In this study of apoB metabolism using a stable isotope method, VLDL-apoB secretion rates were significantly elevated in six FH heterozygous hypercholesterolemic patients relative to control individuals. The important finding in this study was that simvastatin treatment significantly reduced VLDL-apoB secretion by 83%. The decrease in secretion correlated with the decrease in LDL-cholesterol, but not with plasma mevalonate, a measure of cholesterol synthesis.
38. Aguilar-Salinas CA, Barrett PHR, Kelber J, Delmez J, Schonfeld G: Physiologic mechanisms of action of lovastatin in nephrotic syndrome. J Lipid Res 1995, 36:188-199.
39. Aguilar-Salinas CA, Barrett PHR, Pulai J, Zhu, X, Schonfeld G: A familial combined hyperlipidemic kindred with impaired apolipoprotein B catabolism: kinetics of apolipoprotein B during placebo and pravastatin therapy. Arterioscler Thromb Vasc Biol 1997, 17:72-82. This detailed stable-isotope kinetic study investigated the effects of pravastatin on apoB metabolism in a kindred with familial combined hyperlipidemia. This kindred displayed decreased VLDL- and LDL-apoB fractional clearance rates rather than enhanced production rates. Pravastatin significantly increased the LDL-apoB fractional catabolic rate, but had no effect on the low VLDL- or IDL-apoB fractional catabolic rates. No effect on apoB production rates were observed.
40. Forster LF, Stewart G, Bedford DK, Stewart JP, Caslake MJ, Packard CJ, Shepherd J, Black DM: Stable isotope turnover studies of apolipoprotein B in combined hyperlipidemia before and after treatment with atorvastatin, a new HMG-CoA reductase inhibitor [Abstract]. Circulation 1996, 94:1-583.
41. Naoumova RP, Marais AD, Mountney J, Firth JC, Rendell NB, Taylor GW, Thompson GR: Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia. Atherosclerosis 1996, 119:203-213. In individuals heterozygous for FH, pravastatin, simvastatin or atorvastatin reduced plasma LDL-cholesterol in proportion to the decrease in plasma mevalonic acid (a index of cholesterol biosynthesis). Also, the results indicated that the higher the baseline level of plasma mevalonate, the greater was the response in terms of LDL-cholesterol lowering. The same group [42] found a direct correlation between cholesterol synthesis and hepatic VLDL-apoB secretion in normolipidemic individuals, suggesting that inhibition of VLDL-apoB secretion was related to the extent of HMG-CoA reductase inhibition.
42. Watts GF, Naoumova R, Cummings MH, Umpleby AM, Slavin BM, Sönksen PH, Thompson GR: Direct correlation between cholesterol synthesis and hepatic secretion of apolipoprotein B-100 in normolipidemic subjects. Metabolism 1995, 44:1052-1057.
43. Blackhart BD, Ludwig EM, Pierotti VR, Caiati L, Onasch MA, Wallis SC, Powell L, Pease R, Knott TJ, Chu M et al.: Structure of the human apolipoprotein B gene. J Biol Chem 1986, 33:15364-15367.
44. Kardassis D, Zannis VI, Cladaras C: Organization of the regulatory elements and nuclear activities participating in the transcription of the human apolipoprotein B gene. J Biol Chem 1992, 267:2622-2632.
45. Pullinger CR, North JD, Teng B, Rifici VA, Ronhild de Brito AE, Scott J: The apolipoprotein B gene is constitutively expressed in HepG2 cells: regulation of secretion by oleic acid, albumin, and insulin and measurement of the mRNA half-life. J Lipid Res 1989, 30:1065-1077.
46. Sorci-Thomas M, Wilson MD, Johnson GM, Williams DL, Rudel LL: Studies on the expression of genes encoding apolipoproteins B-100 and B-48 and the low density lipoprotein receptor in nonhuman primates. J Biol Chem 1989, 264:9039-9045.
47. Dashti N, Williams DL, Alaupovic P: Effects of oleate and insulin on the production rates and cellular mRNA concentrations of apolipoproteins in HepG2 cells. J Lipid Res 1989, 30:1365-1373.
48. Dixon JL, Ginsberg HN: Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins: information obtained from cultured liver cells. J Lipid Res 1993, 34:167-179.
49. Wu X, Sakata N, Dixon JL, Ginsberg HN: Exogenous VLDL stimulates apolipoprotein B secretion from HepG2 cells by both pre- and posttranslational mechanisms. J Lipid Res 1994, 35:1200-1210.
50. Kohen-Avramoglu R, Cianflone K, Sniderman AD: Role of the neutral lipid accessible pool in the regulation of secretion of apoB-100 lipoprotein particles by HepG2 cells. J Lipid Res 1995, 36:2513-2528. This comprehensive study in HepG2 cells demonstrated that not only newly synthesized cholesteryl ester but also stored cholesteryl ester can associate with newly synthesized apoB and can be secreted without the necessity of an intracellular hydrolysis, re-esterification step.
51. Zhang ZJ, Sniderman AD, Kalant D, Vu J, Monge JC, Tao Y, Cianflone K: The role of amino acids in apoB-100 synthesis and catabolism in human HepG2 cells. J Biol Chem 1993, 268:26920-26926.
52. Cianflone K, Zhang ZJ, Vu H, Kohen-Avramoglu R, Kalant K, Sniderman AD: The effect of individual amino acids on apoB 100 and Lp(a) secretion in HepG2 cells. J Biol Chem 1996, 271:29136-29145.
53. Dashti N: The effect of low density lipoproteins, cholesterol and 25-hydroxycholesterol on apolipoprotein B gene expression in HepG2 cells. J Biol Chem 1992, 267:7160-7169.
54. Selby SL, Yao Z: Level of apolipoprotein B mRNA has an important effect on the synthesis and secretion of apolipoprotein B-containing lipoproteins: studies on transfected hepatoma cell lines expressing recombinant human apolipoprotein B. Arterioscler Thromb Vasc Biol 1995, 15:1900-1910.
55. Dixon JL, Furukawa S, Ginsberg HN: Oleate stimulates secretion of apolipoprotein B-containing lipoproteins from HepG2 cells by inhibiting early intracellular degradation of apolipoprotein B. J Biol Chem 1991, 266:5080-5086.
56. Adeli K: Regulated intracellular degradation of apolipoprotein B in semipermeable HepG2 cells. J Biol Chem 1994, 269:9166-9175.
57. Adeli K, Mohammadi A, Macri J: Regulation of apolipoprotein B biogenesis in human hepatocytes: posttranslational control mechanisms which determine the hepatic production of apolipoprotein B containing lipoproteins. Clin Biochem 1995, 28:123-130.
58. Baonnardel JA, Davis RA: In HepG2 cells, translocation, not degradation, determines the fate of the de novo synthesized apolipoprotein B. J Biol Chem 1995, 270:28892-28896.
59. Musanti R, Giorgini L, Lovisolo P, Pirillo A, Chiari A, Ghiselli G: Inhibition of acyl-CoA : cholesterol acyltransferase decreases apolipoprotein B-100-containing lipoprotein secretion from HepG2 cells. J Lipid Res 1996, 37:1-14.
60. Carr TP, Hamilton Jr RL, Rudel LL: ACAT inhibitors decrease secretion of cholesteryl esters and apolipoprotein B by perfused livers of African green monkeys. J Lipid Res 1995, 36:25-36.
61. Huff MW, Telford DE, Barrett PHR, Billheimer JT, Gillies PJ: Inhibition of hepatic ACAT decreases apoB secretion in miniature pigs fed a cholesterol-free diet. Arterioscler Thromb 1994, 14:1498-1508.
62. Wang H, Germain SJ, Benfield PP, Gillies PJ. Gene expression of acyl coenzyme A : cholesterol acyltransferase is upregulated in human monocytes during differentiation and foam cell formation. Arterioscter Thromb Vasc Biol 1996, 16:809-814.
63. Chang CC, Chen J, Thomas MA, Cheng D, Del Priore VA, Newton RS, Pape ME, Chang TY: Regulation and immunolocalization of acyl-coenzyme A : cholesterol acyltransferase in mammalian cells as studied with specific antibodies. J Biol Chem 1995, 270: 29532-29540.
64. Uelmen PJ, Oka K, Sullivan M, Chang CCY, Chang T, Chan L: Tissue-specific expression and cholesterol regulation of acylcoenzyme A : cholesterol acyltransferase (ACAT) in mice. J Biol Chem 1995, 270:26192-26201.
65. Pape ME, Schultz PA, Rea TJ, DeMattos RB, Kieft K, Bisgaier C, Newton RS, Krause BR: Tissue specific changes in acyl-CoA : cholesterol acyltransferase (ACAT) mRNA levels in rabbits. J Lipid Res 1995, 36:823-838.
66. Ishida F, Sato A, Iizuka Y, Kitani K, Sawasaki Y, Kamei T: Effects of MK-733 (simvastatin). an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on intestinal acyl coenzyme A : cholesterol acyltransferase activity in rabbits. Biochim Biophys Acta 1989, 1004:117-123.
67. Matsuda H, Hakamata H, Miyazaki A, Saki M, Chang CC, Chang TY, Kobori S, Shichiri M, Horiuchi S: Activation of acyl-coenzyme A : cholesterol acyltransferase activity by cholesterol is not due to altered mRNA levels in HepG2 cells. Biochim Biophys Acta 1996, 1301:76-84. Depletion of cholesterol in HepG2 cells with compactin, a HMG-CoA reductase inhibitor, resulted in a decrease in both whole cell and microsomal ACAT activities by 46% and 58%, respectively. ACAT mRNA was unaffected, indicating that regulation of ACAT activity is at a posttranscriptional level.
68. Shand JH, West DW: The effects of simvastatin and cholestyramine, alone and in combination, on hepatic cholesterol metabolism in the male rat. Lipids 1995, 30:917-926. In rats fed diets containing simvastatin, hepatic ACAT activity was reduced by 75%, owing to a decrease in microsomal cholesterol and to a nonsubstrate-dependent decrease in enzyme activity.
69. Jamil N, Dickson JK, Chu C, Lago MW, Rinehart JK, Biller SA, Gregg RE, Wetterau JR: Microsomal triglyceride transfer protein: specificity of lipid binding and transport. J Biol Chem 1995, 270:6549-6554.
70. Wang S, McLeod RS, Gordon DA, Yao Z: The microsomal triglyceride transfer protein facilitates assembly and secretion of apolipoprotein B-containing lipoproteins and decreases cotranslational degradation of apolipoprotein B in transfected COS-7 cells. J Biol Chem 1996, 271:14124-14133. This study demonstrates that transfection of COS-7 cells with the MTP gene results in MTP-facilitated translocation of apoB through the endoplasmic reticulum. This suggests an additional role for MTP in addition to facilitating transfer of lipid to apoB for lipoprotein core assembly.
71. Du EZ, Wang S, Kayden HJ, Sokol R, Curtiss LK, Davis RA: Translocation of apolipoprotein B across the endoplasmic reticulum is blocked in abetalipoproteinemia. J Lipid Res 1996, 37:1309-1315. The absence of MTP results in decreased apoB translocation through the endoplasmic reticulum. This suggests that MTP directly facilitates translocation and that availability of lipid (triglyceride and cholesterol ester), transferred by MTP, may regulate the translocation process.
72. Hagan DL, Kienzle B, Jamil H, Hariharan N: Transcriptional regulation of human and hamster microsomal triglyceride transfer protein genes: cell type-specific expression and response to metabolic regulators. J Biol Chem 1994, 269:28737-28744.
73. Lin MCM, Gordon DA, Wetterau JR: Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: Insulin negatively regulates MTP gene expression. J Lipid Res 1995, 36:1073-1081.
74. Jamil H, Gordon DA, Eustice DC, Brooks CM, Dickson JK Jr, Chen Y, Ricci B, Chu C, Harrity TW, Ciosek CP Jr et al.: An inhibitor of the microsomal triglyceride transfer protein inhibits apoB secretion from HepG2 cells. Proc Natl Acad Sci U S A 1996, 93:11991-11995. An inhibitor of MTP (BMS-200150), when added to HepG2 cells, blocked apoB secretion in a concentration-dependent manner. This study confirmed the essential role of MTP in apoB secretion and, importantly, demonstrates the potential of MTP inhibition as a therapeutic target for reducing hepatic apoB secretion.