MTTP

Official Full Name

microsomal triglyceride transfer protein

Organism

Homo sapiens

GeneID

4547

Background

MTP encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein. Protein disulfide isomerase (PDI) completes the heterodimeric microsomal triglyceride transfer protein, which has been shown to play a central role in lipoprotein assembly. Mutations in MTP can cause abetalipoproteinemia. [provided by RefSeq, Jul 2008]

Synonyms

ABL; MTP;

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Detailed Information

Microsomal triglyceride transporter (MTTP) is involved in lipid transport in lipoprotein assembly, an activity that allows the newly synthesized apoB to bind to triglycerides transported by MTTP into the lumen of the endoplasmic reticulum, and then apoB-containing lipoproteins are transported outside the cell. In addition, MTTP limits the affinity of apoB to ions. Deregulation of MTTP levels and activity directly affects the metabolism of lipids and lipoproteins, which in turn causes many diseases, such as lipid metabolism diseases and cardiovascular diseases. Mutations in the MTTP gene can cause hereditary diseases such as no β-lipoproteinemia. Therefore, the study of MTTP has important clinical significance.

Figure 1. MTTP is required for apoB secretion. (Liu, Y., et al. 2017)

The Structure and Function of MTTP

MTTP includes two subunits: a small protein subsulfide isomerase (PDI) with a relative molecular mass of 58 × 10³ and a unique large subunit of 97 × 10³. In addition to the assembly and transport of lipoproteins in the endoplasmic reticulum, MTTP also has a distribution of two subunits of MTTP in the Golgi apparatus, and the assembly of lipoproteins is more important than its role in the endoplasmic reticulum. The discovery of apoB in the Golgi membrane and the interaction of apoB with the active MTTP indicate an important role for the Golgi in the biological source of apoB lipoprotein.

MTTP and apoB belong to the vitellogenin (VTG) family of lipid transporters. There is a lipid-binding cavity on MTTP, and a helical A fragment and a helical B fragment at the entrance of the MTTP cavity. The function of the helix A (amino acid 725-736) fragment is to regulate lipid collection and binding, and its mutation affects the interaction of MTTP with triglyceride-containing phospholipid vesicles and reduces binding to triglycerides. Mutations in helix B (amino acid 781-786) cause no beta-lipoproteinemia, which does not affect the interaction of MTTP with phospholipid vesicles, but reduces triglyceride binding. It has also been reported that no β-lipoproteinemia is caused by an amino acid error at the C-terminal end of the MTTP large subunit. Insertion of helix A into the lipid membrane is essential for the collection of concentrated lipids, and helix B is required for the binding of triglycerides to the lipid-binding compartment of MTTP.

MTTP and No β-lipoproteinemia

Gene defects and mutations encoding MTTP can cause β-lipoproteinemia. The main manifestations are the absence of apo lipoprotein, VLDL and CM in plasma, the absence of very low LDL or LDL, hypocholesterolemia, and fatty sputum. In patients with MTTP deficiency, N-terminal intact apoB can be seen in plasma. Cell culture experiments showed that apoB transport was blocked when apoB was expressed alone, and it was found that the fragment cut by protease at the N-terminus of apoB was very similar to the fragment found in the plasma of patients without β-lipoproteinemia, suggesting that the patient transports lipoproteins is also suppressed. The pathological mechanism of β-lipoproteinemia may be that when the MTP gene is defective, abnormalities of MTTP molecules lead to dysfunction, lipoprotein molecules cannot be normally assembled and secreted, and lipids cannot be normally metabolized, which causes a decrease in plasma lipids, intracellular lipid accumulation and formation of β-lipoproteinemia.

References:

Liu, Y. , Conlon, D. M. , Bi, X. , Slovik, K. J. , Shi, J. , & Edelstein, H. I. , et al. (2017). Lack of mttp activity in pluripotent stem cell-derived hepatocytes and cardiomyocytes abolishes apob secretion and increases cell stress. Cell Reports, 19(7), 1456-1466.
Haas, M. E.. (2013). The regulation of apob metabolism by insulin. Trends in Endocrinology & Metabolism Tem, 24(8), 391-397.
Di, F. M., Moulin, P., Roy, P., Samsonbouma, M. E., Collardeaufrachon, S., & Chebeldumont, S., et al. (2014). Homozygous mttp and apob mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. Journal of Hepatology, 61(4), 891-902.

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