Microsomal triglyceride transfer protein: molecular genetics, functional mechanisms, and clinical significance
https://doi.org/10.52727/2078-256X-2025-21-4-453-464
Abstract
The aim of this work is to provide a comprehensive review of the structural and functional organization of the MTTP gene and the microsomal triglyceride transfer protein (MTP) it encodes, to characterize its pathogenic variants, and to describe the molecular mechanisms of their action. The MTP is a key regulator of lipid metabolism that is required for the assembly and secretion of apoB‑containing lipoproteins in hepatocytes and enterocytes. Biallelic pathogenic variants in MTTP cause abetalipoproteinemia, a rare life‑threatening disorder with progressive neurological and ophthalmological complications. Several common single nucleotide variants in this gene are associated with various metabolic disturbances. A literature review was conducted, including analysis of the gene structure and mechanisms of alternative splicing of MTTP, the domain organization of MTP, its interaction with protein disulfide isomerase, and selected pathogenic variants of this gene based on published functional studies and clinical data. An in‑depth understanding of the molecular mechanisms underlying MTP dysfunction is essential for accurate interpretation of genetic testing results, prediction of clinical phenotype, differential diagnosis, and the development of personalized therapeutic strategies for abetalipoproteinemia and related disorders.
Keywords
MTTP gene,
microsomal triglyceride transfer protein,
protein disulfide isomerase,
abetalipoproteinemia,
genetic variants
Supporting agencies: This research was conducted with the financial support of the State Budget Project FWNR2022-0021.
About the Authors
A. S. Asekritova
Government Autonomous Institution of the Republic of Sakha (Yakutia) "Republican Clinical Hospital No.3;
Federal State Autonomous Educational Institution of Higher Education «M.K. Ammosov Northeastern Federal University»
Russian Federation
Russian Federation
Alexandra S. Asekritova, head of center for predictive medicine and bioinformatics, сandidate of medical sciences, associate professor of the Department of therapy, Institute of Medicine
94, Gorkogo ыt., Yakutsk, Republic of Sakha (Yakutia), 677027
58, Belinskogo st., Yakutsk, Republic of Sakha (Yakutia), 677000
A. V. Pavlova
Government Autonomous Institution of the Republic of Sakha (Yakutia) "Republican Clinical Hospital No.3
Russian Federation
Russian Federation
Anna V. Pavlova, chief cardiologist of center for predictive medicine and bioinformatics
94, Gorkogo ыt., Yakutsk, Republic of Sakha (Yakutia), 677027
S. V. Mikhailova
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
Svetlana V. Mikhailova, researcher at the laboratory of human molecular genetics
10, Lavrentyeva ave., Novosibirsk, 630090
D. E. Ivanoshchuk
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
Dinara E. Ivanoshchuk, junior researcher at the laboratory of human molecular genetics
10, Lavrentyeva ave., Novosibirsk, 630090
References
1. Hussain M.M., Shi J., Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J. Lipid Research, 2003; 44 (1): 22–32. doi: 10.1194/jlr.R200014-JLR200
2. Rustaeus S., Stillemark P., Lindberg K., Gordon D., Olofsson S.O. The microsomal triglyceride transfer protein catalyzes the post-translational assembly of apolipoprotein B-100 very low density lipoprotein in McA-RH7777 cells. J. Biol. Chem., 1998; 273 (9): 5196–5203. doi: 10.1074/jbc.273.9.5196
3. Hussain M.M. A proposed model for the assembly of chylomicrons. Atherosclerosis, 2000; 148 (1): 1–15. doi: 10.1016/s0021-9150(99)00397-4
4. Raabe M., Veniant M.M., Sullivan M.A., Zlot C.H., Björkegren J., Nielsen L.B., Wong J.S., Hamilton R.L., Young S.G. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J. Clin. Investigat., 1999; 103 (9): 1287–1298. doi: 10.1172/JCI6576
5. Jamil H., Dickson J.K., Jr., Chu C.H., Lago M.W., Rinehart J.K., Biller S.A., Gregg R.E., Wetterau J.R. Microsomal triglyceride transfer protein. Specificity of lipid binding and transport. J. Biol. Chem., 1995; 270 (12): 6549–6554. doi: 10.1074/jbc.270.12.6549
6. Bassen F.A., Kornzweig A.L. Malformation of the erythrocytes in a case of atypical retinitis pigmentosa. Blood., 1950; 5 (4): 381–387. doi: 10.1182/blood.V5.4.381.381
7. Burnett J.R., Bell D.A., Hooper A.J., Hegele R.A. Clinical utility gene card for: Abetalipoproteinaemia – Update 2014. Eur. J. Hum. Genet., 2015; 23 (6): 890. doi: 10.1038/ejhg.2014.224
8. Hentati F., El-Euch G., Bouhlal Y., Amouri R. Ataxia with vitamin E deficiency and abetalipoproteinemia. Handb. Clin. Neurol., 2012; 103: 295–305. doi: 10.1016/B978-0-444-51892-7.00018-8
9. Lee J., Hegele R.A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J. Inherit. Metab. Dis., 2014; 37 (3): 333–339. doi: 10.1007/s10545-013-9665-4
10. Takahashi M., Okazaki H., Ohashi K., Ogura M., Ishibashi S., Okazaki S., Hirayama S., Hori M., Matsuki K., Yokoyama S., Harada-Shiba M. Current Diagnosis and Management of Abetalipoproteinemia. J. Atheroscler. Thromb., 2021; 28 (10): 1009–1019. doi: 10.5551/jat.RV17056
11. Rodríguez Gutiérrez P.G., González García J.R., Castillo de León Y.A., Zárate Guerrero J.R., Magaña Torres M.T. A novel p.Gly417Valfs*12 mutation in the MTTP gene causing abetalipoproteinemia: Presentation of the first patient in Mexico and analysis of the previously reported cases. J. Clin. Lab. Anal., 2021; 35 (3): e23672. doi: 10.1002/jcla.23672
12. Sharp D., Ricci B., Kienzle B., Lin M.C., Wetterau J.R. Human microsomal triglyceride transfer protein large subunit gene structure. Biochemistry, 1994; 33(31): 9057–9061. doi: 10.1021/bi00197a005
13. Suzuki T., Swift L.L. Discovery of Novel Splice Variants and Regulatory Mechanisms for Microsomal Triglyceride Transfer Protein in Human Tissues. Sci. Rep., 2016; 6: 27308. doi: 10.1038/srep27308
14. Biterova E.I., Isupov M.N., Keegan R.M., Lebedev A.A., Sohail A.A., Liaqat I., Alanen H.I., Ruddock L.W. The crystal structure of human microsomal triglyceride transfer protein. Proc. Natl. Acad. Sci. USA., 2019; 116 (35): 17251–17260. doi: 10.1073/pnas.1903029116
15. Rehberg E.F., Samson-Bouma M.E., Kienzle B., Blinderman L., Jamil H., Wetterau J.R., Aggerbeck L.P., Gordon D.A. 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. J. Biol. Chem., 1996; 271 (47): 29945–29952. doi: 10.1074/jbc.271.47.29945
16. Hussain M.M., Rava P., Walsh M., Rana M., Iqbal J. Multiple functions of microsomal triglyceride transfer protein. Nutr. Metab. (Lond.), 2012; 9: 14. doi: 10.1186/1743-7075-9-14
17. Wetterau J.R., Combs K.A., Spinner S.N., Joiner B.J. Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex. J. Biol. Chem., 1990; 265,(17): 9800–9807
18. Klappa P., Ruddock L.W., Darby N.J., Freedman R.B. The b’ domain provides the principal peptide-binding site of protein disulfide isomerase but all domains contribute to binding of misfolded proteins. EMBO J., 1998; 17 (4): 927–935. doi: 10.1093/emboj/17.4.927
19. Ellgaard L., Ruddock L.W. The human protein disulphide isomerase family: substrate interactions and functional properties. EMBO Rep., 2005; 6 (1): 28–32. doi: 10.1038/sj.embor.7400311
20. Chen F., Yang A., Lu Y., Zhang Y., Zhang J., Bu J., Guo R., Han Y., Wu D., Wu Y. Differential transport pathways of saturated and unsaturated fatty acid esters in male mouse hepatocytes. Nat. Commun., 2025; 16 (1): 1344. doi: 10.1038/s41467-025-56620-4
21. Munro S., Pelham H.R. A C-terminal signal prevents secretion of luminal ER proteins. Cell, 1987; 48 (5): 899–907. doi: 10.1016/0092-8674(87)90086-9
22. Mann C.J., Anderson T.A., Read J., Chester S.A., Harrison G.B., Köchl S., Ritchie P.J., Bradbury P., Hussain F.S., Amey J., Vanloo B., Rosseneu M., Infante R., Hancock J.M., Levitt D.G., Banaszak L.J., Scott J., Shoulders C.C. The structure of vitellogenin provides a molecular model for the assembly and secretion of atherogenic lipoproteins. J. Mol. Biol., 1999; 285 (1): 391–408. doi: 10.1006/jmbi.1998.2298
23. Bradbury P., Mann C.J., Köchl S., Anderson T.A., Chester S.A., Hancock J.M., Ritchie P.J., Amey J., Harrison G.B., Levitt D.G., Banaszak L.J., Scott J., Shoulders C.C. A common binding site on the microsomal triglyceride transfer protein for apolipoprotein B and protein disulfide isomerase. J. Biol. Chem., 1999; 274 (5): 3159–3164. doi: 10.1074/jbc.274.5.3159
24. Rustaeus S., Stillemark P., Lindberg K., Gordon D., Olofsson S.O. The microsomal triglyceride transfer protein catalyzes the post-translational assembly of apolipoprotein B-100 very low density lipoprotein in McA-RH7777 cells. J. Biol. Chem., 1998; 273 (9): 5196–5203. doi: 10.1074/jbc.273.9.5196
25. Sirwi A., Hussain M.M. Lipid transfer proteins in the assembly of apoB-containing lipoproteins. J. Lipid. Res., 2018; 59 (7): 1094–1102. doi: 10.1194/jlr.R083451
26. Thierer J.H., Foresti O., Yadav P.K., Wilson M.H., Moll T.O.C., Shen M.C., Busch-Nentwich E.M., Morash M., Mohlke K.L., Rawls J.F., Malhotra V., Hussain M.M., Farber S.A. Pla2g12b drives expansion of triglyceride-rich lipoproteins. Nat. Commun., 2024; 15 (1): 2095. doi: 10.1038/s41467-024-46102-4
27. Fisher E., Lake E., McLeod R.S. Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion. J. Biomed. Res., 2014; 28 (3): 178–193. doi: 10.7555/JBR.28.20140019
28. Iqbal J., Walsh M.T., Hammad S.M., Cuchel M., Tarugi P., Hegele R.A., Davidson N.O., Rader D.J., Klein R.L., Hussain M.M. Microsomal Triglyceride Transfer Protein Transfers and Determines Plasma Concentrations of Ceramide and Sphingomyelin but Not Glycosylceramide. J. Biol. Chem., 2015; 290 (43): 25863–25875. doi: 10.1074/jbc.M115.659110
29. Rader D.J., Brewer H.B., Jr. Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease. JAMA, 1993; 270 (7): 865–869. doi: 10.1001/jama.270.7.865
30. Valmiki S., Bredefeld C., Hussain M.M. A novel mutation, Ile344Asn, in microsomal triglyceride transfer protein abolishes binding to protein disulfide isomerase. J. Lipid. Res., 2025; 66 (1): 100725. doi: 10.1016/j.jlr.2024.100725
31. Benayoun L., Granot E., Rizel L., Allon-Shalev S., Behar D.M., Ben-Yosef T. Abetalipoproteinemia in Israel: evidence for a founder mutation in the Ashkenazi Jewish population and a contiguous gene deletion in an Arab patient. Mol. Genet. Metab., 2007; 90 (4): 453–457. doi: 10.1016/j.ymgme.2006.12.010
32. Ricci B., Sharp D., O’Rourke E., Kienzle B., Blinderman L., Gordon D., Smith-Monroy C., Robinson G., Gregg R.E., Rader D.J., Wetterau J.R. A 30-amino acid truncation of the microsomal triglyceride transfer protein large subunit disrupts its interaction with protein disulfide-isomerase and causes abetalipoproteinemia. J. Biol. Chem., 1995; 270 (24): 14281–14285. doi: 10.1074/jbc.270.24.14281
33. Walsh M.T., Iqbal J., Josekutty J., Soh J., Di Leo E., Özaydin E., Gündüz M., Tarugi P., Hussain M.M. Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal β-Barrel in Microsomal Triglyceride Transfer Protein Function. Circ. Cardiovasc. Genet., 2015; 8 (5): 677–687. doi: 10.1161/CIRCGENETICS.115.001106
34. Khatun I., Walsh M.T., Hussain M.M. Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia. J. Lipid. Res., 2013; 54 (6): 1541–1549. doi: 10.1194/jlr.M031658
35. Miller S.A., Burnett J.R., Leonis M.A., McKnight C.J., van Bockxmeer F.M., Hooper A.J. Novel missense MTTP gene mutations causing abetalipoproteinemia. Biochim. Biophys. Acta., 2014; 1842 (10): 1548–1554. doi: 10.1016/j.bbalip.2014.08.001
36. Di Filippo M., Varret M., Boehm V., Rabès J.P., Ferkdadji L., Abramowitz L., Dumont S., Lenaerts C., Boileau C., Joly F., Schmitz J., Samson-Bouma M.E., Bonnefont-Rousselot D. Postprandial lipid absorption in seven heterozygous carriers of deleterious variants of MTTP in two abetalipoproteinemic families. J. Clin. Lipidol., 2019; 13 (1): 201–212. doi: 10.1016/j.jacl.2018.10.003
37. Paquette M., Dufour R., Hegele R.A., Baass A. A tale of 2 cousins: An atypical and a typical case of abetalipoproteinemia. J. Clin. Lipidol., 2016; 10 (4): 1030–1034. doi: 10.1016/j.jacl.2016.01.003
38. Di Filippo M., Créhalet H., Samson-Bouma M.E., Bonnet V., Aggerbeck L.P., Rabès J.P., Gottrand F., Luc G., Bozon D., Sassolas A. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia. J. Lipid. Res., 2012; 53 (3): 548–555. doi: 10.1194/jlr.M020024
39. Wang J., Hegele R.A. Microsomal triglyceride transfer protein (MTP) gene mutations in Canadian subjects with abetalipoproteinemia. Hum. Mutat., 2000; 15 (3): 294–295. doi: 10.1002/(SICI)1098-1004(200003)15:3<294::AID-HUMU14>3.0.CO;2-E
40. Ohashi K., Ishibashi S., Osuga J., Tozawa R., Harada K., Yahagi N., Shionoiri F., Iizuka Y., Tamura Y., Nagai R., Illingworth D.R., Gotoda T., Yamada N. Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia. J. Lipid. Res., 2000; 41 (8): 1199–1204
41. Gurram S., Holla V.V., Sriram N., Phulpagar P., Jha S., Sharma P., Mallithavana S., Kamble N., Netravathi M., Yadav R., Muthusamy B., Pal P.K. A Rare Case of Ophthalmoplegia with Ataxia in Genetically Proven Abetalipoproteinemia. Mov. Disord. Clin. Pract., 2022; 10 (3): 514–517. doi: 10.1002/mdc3.13626
42. Grove J.I., Lo P.C.K., Shrine N., Barwell J., Wain L.V., Tobin M.D., Salter A.M., Borkar A.N., Cuevas-Ocaña S., Bennett N., John C., Ntalla I., Jones G.E., Neal C.P., Thomas M.G., Kuht H., Gupta P., Vemala V.M., Grant A., Adewoye A.B., Shenoy K.T., Balakumaran L.K., Hollox E.J., Hannan N.R.F., Aithal G.P. Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease. JHEP Rep., 2023; 5 (8): 100764. doi: 10.1016/j.jhepr.2023.100764
43. Sasaki K., Tada H., Komatsu T., Terada H., Endo Y., Ikewaki K., Uehara Y. A New Case of Abetalipoproteinemia Caused by Novel Compound Heterozygote Mutations in the MTTP Gene without Fat or Vitamin Malabsorption. J. Atheroscler. Thromb., 2024; 31 (11): 1634–1640. doi: 10.5551/jat.64730
44. Gouda W., Ashour E., Shaker Y., Ezzat W. MTP genetic variants associated with non-alcoholic fatty liver in metabolic syndrome patients. Genes Dis., 2017; 4 (4): 222–228. doi: 10.1016/j.gendis.2017.09.002
45. Peng X.E., Wu Y.L., Lu Q.Q., Hu Z.J., Lin X. MTTP polymorphisms and susceptibility to non-alcoholic fatty liver disease in a Han Chinese population. Liver Int., 2014; 34 (1): 118–128. doi: 10.1111/liv.12220
46. Ledmyr H., McMahon A.D., Ehrenborg E., Nielsen L.B., Neville M., Lithell H., MacFarlane P.W., Packard C.J., Karpe F.; WOSCOPS executive. The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease. Circulation. 2004; 109 (19): 2279–2284. doi: 10.1161/01.CIR.0000130070.96758.7b
47. di Giuseppe R., Pechlivanis S., Fisher E., Arregui M., Weikert B., Knüppel S., Buijsse B., Fritsche A., Willich S.N., Joost H.G., Boeing H., Moebus S., Weikert C. Microsomal triglyceride transfer protein -164 T > C gene polymorphism and risk of cardiovascular disease: results from the EPIC-Potsdam case-cohort study. BMC Med. Genet., 2013; 14: 19. doi: 10.1186/1471-2350-14-19
48. Rubin D., Helwig U., Pfeuffer M., Schreiber S., Boeing H., Fisher E., Pfeiffer A., Freitag-Wolf S., Foelsch U.R., Doering F., Schrezenmeir J. A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels. J. Hum. Genet., 2006; 51 (6): 567–574. doi: 10.1007/s10038-006-0400-y
49. Wang X., Cao Y., Guo J., Li D., Zhang H., Song Q., Lu J. Association between MTTP genotype (-493G/T) polymorphism and hepatic steatosis in hepatitis C: a systematic review and meta-analysis. Lipids Health Dis., 2023; 22 (1): 154. doi: 10.1186/s12944-023-01916-x
Review
For citations:
Asekritova A.S., Pavlova A.V., Mikhailova S.V., Ivanoshchuk D.E. Microsomal triglyceride transfer protein: molecular genetics, functional mechanisms, and clinical significance. Ateroscleroz. 2025;21(4):453-464. (In Russ.) https://doi.org/10.52727/2078-256X-2025-21-4-453-464
Views:
56
JATS XML
Email this article 
