Microsomal triglyceride transfer protein explained

Microsomal triglyceride transfer protein should not be confused with mitochondrial trifunctional protein.

Microsomal triglyceride transfer protein large subunit is a protein that in humans is encoded by the MTTP, also known as MTP, gene.^{[1] [2]}

MTTP encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein (MTP). Protein disulfide isomerase (PDI) completes the heterodimeric MTP, which has been shown to play a central role in lipoprotein assembly. Mutations in MTTP can cause abetalipoproteinemia.

Apolipoprotein B48 on chylomicra and Apolipoprotein B100 on LDL, IDL, and VLDL are important for MTP binding.

MTP adds triglycerides to nascent chylomicrons in the intestine, and to VLDL in the liver.^[3]

Structure

The large subunit of MTP, also known as the alpha subunit, contains an N-terminal half beta barrel, an alpha helix and a C-terminal lipid binding site that lies between two beta pleated sheets. It is a member of the large lipid transfer protein family, like apolipoprotein B (apo B), with which it interacts, but unlike apo B, it is not secreted. The heterodimer is instead retained in the endoplasmic reticulum due to the presence of a C-terminal KDEL motif on the PDI beta subunit.^[4]

Pharmacology

Drugs that inhibit MTTP prevent the assembly of apo B-containing lipoproteins thus inhibiting the synthesis of chylomicrons and VLDL and leading to decrease in plasma levels of LDL-C.

• Lomitapide (Juxtapid) was approved by the US FDA for adjunctive treatment of homozygous familial hypercholesterolemia.
• Dirlotapide (Slentrol) and mitratapide (Yarvitan) are veterinary drugs for the management of obesity in dogs.

Further reading

• Book: Luz JM, Lennarz WJ . Stress-Inducible Cellular Responses . Protein disulfide isomerase: A multifunctional protein of the endoplasmic reticulum . Experientia Supplementum. Feige U, Yahara I, Morimoto RI, Polla BS. 77 . 97–117 . 1996 . 8856971 . 10.1007/978-3-0348-9088-5_7. 978-3-0348-9901-7 .
• Wetterau JR, Lin MC, Jamil H . Microsomal triaglyceride transfer protein. . Biochim. Biophys. Acta . 1345 . 2 . 136–50 . 1997 . 9106493 . 10.1016/s0005-2760(96)00168-3 .
• Gordon DA . Recent advances in elucidating the role of the microsomal triaglyceride transfer protein in apolipoprotein B lipoprotein assembly. . Curr. Opin. Lipidol. . 8 . 3 . 131–7 . 1997 . 9211060 . 10.1097/00041433-199706000-00002 .
• Ye J . Reliance of Host Cholesterol Metabolic Pathways for the Life Cycle of Hepatitis C Virus . PLOS Pathog. . 3 . 8 . e108 . 2007 . 17784784 . 10.1371/journal.ppat.0030108 . 1959368 . free .
• Wetterau JR, Aggerbeck LP, Bouma ME, etal . Absence of microsomal triaglyceride transfer protein in individuals with abetalipoproteinemia . Science . 258 . 5084 . 999–1001 . 1992 . 1439810 . 10.1126/science.1439810 . 1992Sci...258..999W .
• Sharp D, Ricci B, Kienzle B, etal . Human microsomal triaglyceride transfer protein large subunit gene structure . Biochemistry . 33 . 31 . 9057–61 . 1994 . 7545943 . 10.1021/bi00197a005 .
• Shoulders CC, Narcisi TM, Read J, etal . The abetalipoproteinemia gene is a member of the vitellogenin family and encodes an alpha-helical domain . Nat. Struct. Biol. . 1 . 5 . 285–6 . 1995 . 7664034 . 10.1038/nsb0594-285 . 11860468 .
• Hagan DL, Kienzle B, Jamil H, Hariharan N . Transcriptional regulation of human and hamster microsomal triaglyceride transfer protein genes. Cell type-specific expression and response to metabolic regulators . J. Biol. Chem. . 269 . 46 . 28737–44 . 1994 . 10.1016/S0021-9258(19)61967-8 . 7961826 . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Sharp D, Blinderman L, Combs KA, etal . Cloning and gene defects in microsomal triaglyceride transfer protein associated with abetalipoproteinaemia . Nature . 365 . 6441 . 65–9 . 1993 . 8361539 . 10.1038/365065a0 . 1993Natur.365...65S . 4334532 .
• Narcisi TM, Shoulders CC, Chester SA, etal . Mutations of the Microsomal Triglyceride-Transfer–Protein Gene in Abetalipoproteinemia . Am. J. Hum. Genet. . 57 . 6 . 1298–310 . 1996 . 8533758 . 1801399 .
• Rehberg EF, Samson-Bouma ME, Kienzle B, etal . A novel abetalipoproteinemia genotype. Identification of a missense mutation in the 97-kDa subunit of the microsomal triaglyceride transfer protein that prevents complex formation with protein disulfide isomerase . J. Biol. Chem. . 271 . 47 . 29945–52 . 1997 . 8939939 . 10.1074/jbc.271.47.29945 . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, etal . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Linnik KM, Herscovitz H . Multiple molecular chaperones interact with apolipoprotein B during its maturation. The network of endoplasmic reticulum-resident chaperones (ERp72, GRP94, calreticulin, and BiP) interacts with apolipoprotein b regardless of its lipidation state . J. Biol. Chem. . 273 . 33 . 21368–73 . 1998 . 9694898 . 10.1074/jbc.273.33.21368 . free .
• Bradbury P, Mann CJ, Köchl S, etal . A common binding site on the microsomal triaglyceride transfer protein for apolipoprotein B and protein disulfide isomerase . J. Biol. Chem. . 274 . 5 . 3159–64 . 1999 . 9915855 . 10.1074/jbc.274.5.3159 . free .
• Wang J, Hegele RA . Microsomal triaglyceride transfer protein (MTP) gene mutations in Canadian subjects with abetalipoproteinemia . Hum. Mutat. . 15 . 3 . 294–5 . 2000 . 10679949 . 10.1002/(SICI)1098-1004(200003)15:3<294::AID-HUMU14>3.0.CO;2-E . free .

Notes and References

1. Shoulders CC, Brett DJ, Bayliss JD, Narcisi TM, Jarmuz A, Grantham TT, Leoni PR, Bhattacharya S, Pease RJ, Cullen PM . Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein . Hum Mol Genet . 2 . 12 . 2109–16 . Mar 1994 . 8111381 . 10.1093/hmg/2.12.2109 . etal.
2. Web site: Entrez Gene: MTTP microsomal triglyceride transfer protein.
3. Book: Katzung, Bertram G. . Basic & Clinical Pharmacology . McGraw-Hill Education . 2018 . 978-1-259-64115-2 . 14th . 2018 . 638.
4. Biterova EI, Isupov MN, Keegan RM, Lebedev AA, Sohail AA, Liaquat I, Alanen HI, Ruddock LW. Proceedings of the National Academy of Sciences of the United States of America. 116. 35. 17251–17260. 10.1073/pnas.1903029116. free. 2019. The crystal structure of human microsomal triglyceride transfer protein. 31395737. 6717300. 2019PNAS..11617251B .