Hostname: page-component-8448b6f56d-sxzjt Total loading time: 0 Render date: 2024-04-24T00:50:13.974Z Has data issue: false hasContentIssue false
  • English
  • Français

The assembly of triacylglycerol-rich lipoproteins: an essential role for the microsomal triacylglycerol transfer protein

Published online by Cambridge University Press:  09 March 2007

David A. White ,
Andrew J. Bennett ,
Michael A. Billett  and
Andrew M. Salter
David A. White*
Affiliation:
School of Biomedical Sciences University of Nottingham, Nottingham NG7 2UH, UK
Andrew J. Bennett
Affiliation:
School of Biomedical Sciences University of Nottingham, Nottingham NG7 2UH, UK
Michael A. Billett
Affiliation:
School of Biomedical Sciences University of Nottingham, Nottingham NG7 2UH, UK
Andrew M. Salter
Affiliation:
School of Biological Sciences, University of Nottingham, Nottingham NG7 2UH, UK
*
*Corresponding author: Dr D. A. White, fax +44 (0)115 942 2225, email david.white@nottingham.ac.uk
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Raised plasma triacylglycerol is an independent risk factor for cardiovascular disease, and an understanding of factors which regulate the synthesis and degradation of lipoproteins which carry triacylglycerol in the blood may lead to novel approaches to the treatment of hypertriacylglycerolaemia. An active microsomal triacylglycerol transfer protein (MTP) is essential for the assembly of particles which transport triacylglycerol through the circulation. After absorption in the intestine, dietary fat and fat-soluble vitamins are incorporated into chylomicrons in the intestinal epithelial cells, and these lipoproteins reach the bloodstream via the lymphatic system. Patients with the rare genetic disorder, abetalipoproteinaemia, in which MTP activity is absent, present clinically with fat-soluble vitamin and essential fatty acid deficiency, indicating a key role for MTP in the movement of fat into the body. The triacylglycerol-rich lipoprotein found in fasting blood, VLDL, is assembled in the liver by an MTP-dependent process similar to chylomicron assembly, and transports triacylglycerol to extra-hepatic tissues such as adipose tissue and heart. In the absence of MTP activity, VLDL are not synthesized and only extremely low levels of triacylglycerol are present in the blood. Dietary components, including fat, cholesterol and ethanol, can modify the expression of the MTP gene and, hence, MTP activity. The present review summarizes current knowledge of the role of MTP in the assembly and secretion of triacylglycerol-rich lipoproteins, and the regulation of its activity in both animal and cell systems.

Keywords

TriacylglycerolsLipoproteinsMicrosomal triacylglycerol transfer proteinApolipoproteinsAbetalipoproteinaemia
Type
Review article
Information
British Journal of Nutrition , Volume 80 , Issue 3 , September 1998 , pp. 219 - 229
Copyright
Copyright © The Nutrition Society 1998

References

Atzel, A & Wetterau, JR (1993) Mechanism of microsomal triglyceride transfer protein catalized lipid transport. Biochemistry 39, 10444–10450.CrossRefGoogle Scholar
Atzel, A & Wetterau, JR (1994) Identification of 2 classes of lipid molecule-binding sites on the microsomal triglyceride transfer protein. Biochemistry 33, 15382–15388.CrossRefGoogle Scholar
Bennett, AJ, Billett, MA, Salter, AM & White, DA (1995) The regulation of hamster hepatic microsomal triglyceride transfer protein messenger-RNA levels by dietary fats. Biochemical and Biophysical Research Communications 212, 473–478.CrossRefGoogle ScholarPubMed
Bennett, AJ, Bruce, JS, Salter, AM, White, DA & Billett, MA (1996) Hepatic-microsomal triglyceride transfer protein messenger-RNA concentrations are increased by dietary-cholesterol in hamsters. FEBS Letters 394, 247–250.CrossRefGoogle ScholarPubMed
Benoist, F & Grand-Perrett, T (1997) Co-translational degradation of apolipoprotein B100 by the proteosome is prevented by microsomal triglyceride transfer protein. Journal of Biological Chemistry 272, 20435–20442.CrossRefGoogle ScholarPubMed
Benoist, F, Nicodeme, E & Grand-Perrett, T (1996) Microsomal triacyglycerol transfer protein prevents presecretory degradation of apolipoprotein B-100. European Journal of Biochemistry 240, 713–720.CrossRefGoogle Scholar
Bonnardel, JA & Davis, RA (1995) In HepG2 cells, translocation, not degradation, determines the fate of the de novo synthesized apolipoprotein B. Journal of Biological Chemistry 270, 28892–28896.CrossRefGoogle Scholar
Borchardt, RA & Davis, RA (1987) Intrahepatic assembly of very low density lipoproteins. Rate of transport out of the endoplasmic reticulum determines rate of secretion. Journal of Biological Chemistry 262, 16394–16402.CrossRefGoogle ScholarPubMed
Boren, J, Rustaeus, S & Olofsson, SO (1994) Studies on the assembly of apolipoprotein-B-100-containing and apolipoprotein-B-48-containing very low density lipoprotein in McA-RH7777 cells. Journal of Biological Chemistry 269, 25879–25888.CrossRefGoogle Scholar
Brett, DJ, Pease, RJ, Scott, J & Gibbons, GF (1995) Microsomal triglyceride transfer protein activity remains unchanged in rat livers under conditions of altered very low density lipoprotein secretion. Biochemical Journal 310, 11–14.CrossRefGoogle ScholarPubMed
Cartwright, IJ & Higgins, JA (1996) Intracellular degradation in the regulation of secretion of apoB-100 by rabbit hepatocytes. Biochemical Journal 314, 377–384.CrossRefGoogle ScholarPubMed
Cartwright, IJ, Higgins, JA, Wilkinson, J, Bellavia, S, Kendrick, JS & Graham, JM (1997) Investigation of the role of lipids in the assembly of very low density lipoproteins in rabbit hepatocytes. Journal of Lipid Research 38, 531–545.CrossRefGoogle ScholarPubMed
Davis, RA, Thrift, RN, Wu, CC & Howell, KE (1990) Apolipoprotein B is both integrated into and translocated across the endoplasmic reticulum membrane. Evidence for two functionally distinct pools. Journal of Biological Chemistry 265, 10005–10011.CrossRefGoogle ScholarPubMed
Dietschy, JM, Turley, SD & Spady, DK (1993) Role of liver in the maintenance of cholesterol and lipoprotein homeostasis in different animal species, including humans. Journal of Lipid Research 34, 1637–1659.CrossRefGoogle ScholarPubMed
Drayna, D, Jarnagin, AS, McLean, J, Henzel, W, Kohr, W, Fielding, C & Lawn, RM (1987) Cloning and sequencing of human cholesteryl ester transfer protein cDNA. Nature 327, 632–634.CrossRefGoogle ScholarPubMed
Du, EZ, Kurth, J, Wand, S-L, Humiston, P & Davis, RA (1994) Proteolysis-coupled secretion of the N-terminus of apolipoprotein B: characterization of a transient, translocation-arrested intermediate. Journal of Biological Chemistry 269, 24169–24176.CrossRefGoogle ScholarPubMed
Du, EZ, Wang, S-L, Kayden, HJ, Sokol, R, Curtiss, LK & Davis, RA (1996) Translocation of apolipoprotein B across the endoplasmic reticulum is blocked in abetalipoproteinemia. Journal of Lipid Research 37, 1309–1315.CrossRefGoogle ScholarPubMed
Fisher, EA, Zhou, M, Mitchell, DM, Wu, X, Omura, S, Goldberg, AL & Ginsberg, HN (1997) The degradation of apolipoprotein B100 is mediated by the ubiquitin-proteosome pathway and involves heat shock protein 70. Journal of Biological Chemistry 272, 20427–20434.CrossRefGoogle Scholar
Gordon, DA (1997) Recent advances in elucidating the role of the microsomal triglyceride transfer protein in apoB lipoprotein assembly. Current Opinion in Lipidology 8, 131–137.CrossRefGoogle Scholar
Gordon, DA, Jamil, H, Gregg, RE, Olofsson, SO & Boren, J (1996) Inhibition of the microsomal triglyceride transfer protein blocks the first step of the apolipoprotein B lipoprotein assembly but not the addition of bulk core lipids in the second step. Journal of Biological Chemistry 271, 33047–33053.CrossRefGoogle Scholar
Gordon, DA, Jamil, H, Sharp, D, Mullaney, D, Yao, ZM, Gregg, RE & Wetterau, J (1994) The secretion of apolipoprotein B-containing lipoproteins from HeLa-cells is dependent on expression of the microsomal triglyceride transfer protein and is regulated by lipid availability. Proceedings of the National Academy of Sciences USA 91, 7628–7632.CrossRefGoogle ScholarPubMed
Gregg, RE & Wetterau, JR (1994) The molecular basis of abetalipoproteinaemia. Current Opinion in Lipidology 5, 81–86.CrossRefGoogle Scholar
Gretch, DG, Sturley, SL, Wang, L, Lipton, BA, Dunning, A, Grunwald, KAA, Wetterau, JR, Yao, ZM, Talmud, P & Attie, AD (1996) The amino-terminus of apolipoprotein-B is necessary but not sufficient for microsomal triglyceride transfer protein responsiveness. Journal of Biological Chemistry 271, 8682–8691.CrossRefGoogle Scholar
Griffin, BA & Zampelas, A (1995) Influence of dietary fatty acids on the atherogenic lipoprotein phenotype. Nutrition Research Reviews 8, 1–26.CrossRefGoogle ScholarPubMed
Hagan, DL, Kienzle, B, Jamil, H & Hariharan, N (1994) Transcriptional regulation of human and hamster microsomal triglyceride transfer protein genes- cell-type specific expression and response to metabolic regulators. Journal of Biological Chemistry 269, 28737–28744.CrossRefGoogle ScholarPubMed
Haghpassand, M, Wilder, D & Moberly, JB (1996) Inhibition of apolipoprotein B and triglyceride secretion in human hepatoma cells (HepG2). Journal of Lipid Research 37, 1468–1480.CrossRefGoogle ScholarPubMed
Ingram, MF & Shelness, GS (1997) Folding of the amino-terminal domain of apolipoprotein B initiates microsomal triglyceride transfer protein-dependent lipid transfer to nascent very low density lipoprotein. Journal of Biological Chemistry 272, 10279–10286.CrossRefGoogle ScholarPubMed
Ivessa, NE, Rehberg, E, Kienzle, B, Seif, F, Recheis, B, Hermann, M, Schneider, WJ & Gordon, DA (1996) Cloning and expression of the chicken microsomal triglyceride transfer protein (MTP). Molecular Biology of the Cell 7, 776 Abstr.Google Scholar
Jamil, H, Dickson, JK, Chu, CH, Lago, MW, Rinehart, JK, Biller, SA, Gregg, RE & Wetterau, JR (1995) Microsomal triglyceride transfer protein- specificity of lipid binding and transport. Journal of Biological Chemistry 270, 6549–6554.CrossRefGoogle ScholarPubMed
Jamil, H, Gordon, DA, Eustice, DC, Brooks, CM, Dickson, JK, Chen, Y, Ricci, B, Chu, CH, Harrity, TW, Ciosek, CP, Biller, SA, Gregg, RE & Wetterau, JR (1996) An inhibitor of the microsomal triglyceride transfer protein inhibits apo-B secretion from HepG2 cells. Proceedings of the National Academy of Sciences USA 93, 11991–11995.CrossRefGoogle ScholarPubMed
Lamberg, A, Juahiainen, M, Metso, J, Ehnholm, C, Shoulders, C, Scott, J, Pihlajaniemi, T & Kivirikko, KI (1996) The role of protein disulfide isomerase in the microsomal triacylglycerol transfer protein does not reside in its isomerase activity. Biochemical Journal 315, 533–536.CrossRefGoogle Scholar
Leiper, JM, Bayliss, JD, Pease, RJ, Brett, DJ, Scott, J & Shoulders, CC (1994) Microsomal triglyceride transfer protein, the abetalipoproteinemia gene-product, mediates the secretion of apolipoprotein B-containing lipoproteins from heterologous cells. Journal of Biological Chemistry 269, 21951–21954.CrossRefGoogle ScholarPubMed
Lin, MCM, Arbeeny, C, Bergquist, K, Kienzle, B, Gordon, DA & Wetterau, JR (1994) Cloning and regulation of hamster micro-somal triglyceride transfer protein- the regulation is independent from that of other hepatic and intestinal proteins which participate in the transport of fatty acids and triglycerides. Journal of Biological Chemisty 269, 29138–29145.CrossRefGoogle ScholarPubMed
Lin, MCM, Gordon, DA & Wetterau, JR (1995) Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells-insulin negatively regulates MTP gene-expression. Journal of Lipid Research 36, 1073–1081.CrossRefGoogle ScholarPubMed
Lin, MCM, Li, J, Wang, E, Princler, GL, Kauffman, FC & Kung, H (1997) Ethanol down-regulates the transcription of microsomal triglyceride transfer protein gene. FASEB Journal 11, 1145–1152.CrossRefGoogle ScholarPubMed
McLeod, RS, Wang, Y, Wang, S, Rusinol, A, Links, P & Yao, Z (1996) Apolipoprotein B sequence requirements for hepatic very low density lipoprotein assembly. Journal of Biological Chemistry 271, 18445–18455.CrossRefGoogle ScholarPubMed
Nakamuta, M, Chang, BHJ, Hoogeveen, R, Li, WH, & Chan, L (1996) Mouse microsomal triglyceride transfer protein large subunit-cDNA cloning, tissue-specific expression, and chromosomal localization. Genomics 33, 313–316.CrossRefGoogle ScholarPubMed
Narcisi, TME, Shoulders, CC, Chester, SA, Read, J, Brett, DJ, Harrison, GB, Grantham, TT, Fox, MF, Povey, S, Debruin, TWA, Erkelens, DW, Muller, DPR, Lloyd, JK & Scott, J (1995) Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia. American Journal of Human Genetics 57, 1298–1310.Google ScholarPubMed
Patel, SB & Grundy, SM (1996) Interactions between microsomal triglyceride transfer protein and apolipoprotein-B within the endoplasmic-reticulum in a heterologous expression system. Journal of Biological Chemistry 271, 18686–18694.CrossRefGoogle Scholar
Pease, RJ, Harrison, GB & Scott, J (1991) Cotranslational insertion of apolipoprotein-B into the inner leaflet of the endoplasmic reticulum. Nature 353, 448–450.CrossRefGoogle Scholar
Pihlajaniemi, T, Helaakoski, T, Tasanen, K, Myllyla, R, Huhtala, M-L, Koivu, J & Kivirikko, KI (1987) Molecular cloning of the β-subunit of human prolyl 4-hydroxylase. This subunit and protein disulfide isomerase are products of the same gene. EMBO Journal 6, 643–649.CrossRefGoogle ScholarPubMed
Rehberg, EF, Samsonbouma, ME, Kienzle, B, Blinderman, L, Jamil, H, Wetterau, JR, Aggerbeck, LP & Gordon, DA (1996) A novel abetalipoproteinemia genotype- identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex-formation with protein disulfide-isomerase. Journal of Biological Chemistry 271, 29945–29952.CrossRefGoogle ScholarPubMed
Ricci, B, Sharp, D, O'Rourke, E, Kienzle, B, Blinderman, L, Gordon, D, Smithmonroy, C, Robinson, G, Gregg, RE, Rader, DJ & Wetterau, JR (1995) A 30-amino acid truncation of the micro-somal triglyceride transfer protein large subunit disrupts its interaction with protein disulfide-isomerase and causes abetalipoproteinemia. Journal of Biological Chemistry 270, 14281–14285.CrossRefGoogle ScholarPubMed
Rueckert, DG & Schmidt, K (1990) Lipid transfer proteins. Chemistry and Physics of Lipids 56, 1–20.CrossRefGoogle ScholarPubMed
Rustaeus, S, Lindberg, K, Boren, J & Oloffson, S-O (1995) Brefeldin A reversibly inhibits the assembly of apoB containing lipoproteins in McA-RH7777 cells. Journal of Biological Chemistry 270, 28879–28886.CrossRefGoogle ScholarPubMed
Salter, AM & White, DA (1996) Effects of dietary fat on cholesterol metabolism: regulation of plasma LDL concentrations. Nutrition Research Reviews 9, 241–257.CrossRefGoogle ScholarPubMed
Sessions, VA, Martin, A, Gomez-Munoz, A, Brindley, DN & Salter, AM (1993) Cholesterol feeding induces hypertriglyceridaemia in hamsters and increases the activity of Mg2+-dependent phosphatidate phosphohydrolase in the liver. Biochemica et Biophysica Acta 1166, 238–243.CrossRefGoogle Scholar
Sharp, D, Blinderman, L, Combs, KA, Kienzle, B, Ricci, B, Wager-smith, K, Gil, CM, Turck, CW, Bouma, ME, Rader, DJ, Aggerbeck, LP, Gregg, RE, Gordon, DA & Wetterau, JR (1993) Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinemia. Nature 365, 65–69.CrossRefGoogle Scholar
Sharp, D, Ricci, B, Kienzle, B, Lin, MCM & Wetterau, JR (1994) Human microsomal triglyceride transfer protein large subunit gene structure. Biochemistry 33, 9057–9061.CrossRefGoogle ScholarPubMed
Shoulders, CC, Brett, DJ, Bayliss, JD, Narcisi, TME, Jarmuz, A, Grantham, TT, Leoni, PRD, Bhattacharya, S, Pease, RJ, Cullen, PM, Levi, S, Byfield, PGH, Purkiss, P & Scott, J (1993) Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of the microsomal triglyceride transfer protein. Human Molecular Genetics 2, 2109–2116.CrossRefGoogle ScholarPubMed
Sniderman, AD, Shapiro, S, Marpole, D, Skinner, B, Teng, B & Kwiterovich, PO (1980) Association of coronary atherosclerosis with hyperapobetalipoproteinemia (increased protein but normal cholesterol levels in human plasma low density lipoproteins). Proceedings of the National Academy of Sciences USA 77, 604–608.CrossRefGoogle Scholar
Teng, B, Sniderman, AD, Soutar, AK & Thompson, GR (1986) Metabolic basis of hyperapobetalipoproteinemia: turnover of apolipoprotein B in low density lipoprotein and its precursors and subfractions compared with normal and familial hypercholesterolemia. Journal of Clinical Investigation 77, 663–672.CrossRefGoogle ScholarPubMed
van Greevenbroek, MMJ, Robertus-Teunissen, MG, Erkelens, DW & de, Bruin TWA (1998) Participation of the microsomal triglyceride transfer protein in lipoprotein assembly in Caco-2 cells: interaction with saturated and unsaturated fatty acids. Journal of Lipid Research 39, 173–185.CrossRefGoogle Scholar
Venkatesan, S, Cullen, P, Pacy, P, Halliday, D & Scott, J (1993) Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia. Arteriosclerosis and Thrombosis 13, 1110–1118.CrossRefGoogle ScholarPubMed
Vuori, K, Pihlajaniemi, T, Mullyla, R & Kivirikko, KI (1992) Site-directed mutagenesis of human protein disulfide isomerase-effect on the assembly, activity and endoplasmic reticulum retention of human prolyl 4-hydroxylase in Spodoptera frugiperda insect cells. EMBO Journal 11, 4213–4217.CrossRefGoogle ScholarPubMed
Wang, S, McLeod, RS, Gordon, DA & Yao, ZM (1996) 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. Journal of Biological Chemistry 271, 14124–14133.CrossRefGoogle ScholarPubMed
Wang, YW, McLeod, RS & Yao, ZM (1997) Normal activity of microsomal triglyceride protein is required for the oleate-induced secretion of very low density lipoproteins containing apoprotein B from McA-RH7777 cells. Journal of Biological Chemistry 272, 12272–12278.CrossRefGoogle ScholarPubMed
Wetterau, JR, Aggerbeck, LP, Bouma, ME, Eisenberg, C, Munck, A, Hermier, M, Schmitz, J, Gay, G, Rader, DJ & Gregg, RE (1992) Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 258, 999–1001.CrossRefGoogle ScholarPubMed
Wetterau, JR, Aggerbeck, LP, Laplaud, PM & McLean, LR (1991 a) Structural properties of the microsomal triglyceride transfer protein complex. Biochemistry 30, 4406–4412.CrossRefGoogle ScholarPubMed
Wetterau, JR, Combs, KA, McLean, LR, Spinner, SN & Aggerbeck, LP (1991 b) Protein disulfide isomerase appears necessary to maintain catalytically active structure of the microsomal triglyceride transfer protein. Biochemistry 30, 9728–9735.CrossRefGoogle ScholarPubMed
Wetterau, JR, Combs, KA, Spinner, SN & Joiner, BJ (1990) Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex. Journal of Biological Chemistry 265, 9800–9807.CrossRefGoogle ScholarPubMed
Wetterau, JR, Lin, MCM & Jamil, H (1997) Microsomal triglyceride transfer protein. Biochimica et Biophysica Acta 1345, 136–150.CrossRefGoogle ScholarPubMed
Wetterau, JR & Zilversmit, DB (1984) A triglyceride and cholesteryl ester transfer protein associated with liver microsomes. Journal of Biological Chemistry 259, 10863–10866.CrossRefGoogle ScholarPubMed
Wetterau, JR & Zilversmit, DB (1985) Purification and characterization of microsomal triglyceride and cholesteryl ester transfer protein from bovine liver microsomes. Chemistry and Physics of Lipids 38, 205–222.CrossRefGoogle ScholarPubMed
Wetterau, JR & Zilversmit, DM (1986) Localization of intracellular triacylglycerol and cholesteryl ester transfer activity in rat tissues. Biochimica et Biophysica Acta 875, 610–617.CrossRefGoogle ScholarPubMed
Wu, ZJ, Zhou, MY, Huang, LS, Wetterau, JR & Ginsberg, HN(1996) Demonstration of a physical interaction between microsomal triglyceride transfer protein and apolipoprotein-B during the assembly of apo-B containing lipoproteins. Journal of Biological Chemistry 271, 10277–10281.CrossRefGoogle Scholar
Zhou, M, Wu, Z, Huang, L-S & Ginsberg, HN (1995) Apolipoprotein B100, an inefficiently translocated secretory protein, is bound to a cytosolic chaperone, heat shock protein 70. Journal of Biological Chemistry 265, 25220–25224.CrossRefGoogle Scholar