Disease relevance of MTTP

• Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia [1].
• We recently observed that a polymorphism in the MTTP promoter (-493G>T), which is in allelic association with an isoleucine-to-theronine substitution at position 128 (Ile128Thr) in the expressed protein, confers an increased risk of coronary heart disease [2].
• In these studies we show that transcriptional co-repression of the two lipid transfer proteins, liver fatty acid-binding protein (L-FABP) and MTP, which cooperatively shunt fatty acids into de novo synthesized glycerolipids and the transfer of lipids into VLDL, respectively, act together to maintain hepatic lipid homeostasis [3].
• Studies carried out in a variety of heterologous expression systems, as well as the use of microsomal triglyceride transfer protein inhibitors in hepatoma cell lines, have been critical to this progress [4].
• These complex regulations may represent a means to fine-tuning MTP gene transcription in response to a diverse set of environmental stimuli and may have important implications for the onset and development of diabetes-associated dyslipidemia [5].
• MTP -493 G/T polymorphism may impact NASH by modulating postprandial lipemia and lipoprotein metabolism; homozygous GG carriers have a more atherogenic postprandial lipid profile than the other genotypes, independently of adipokines and insulin resistance [6].

Psychiatry related information on MTTP

• "Among women attending the MTP [medical termination of pregnancy] clinic of the National Institute of Health and Family Welfare, New Delhi [India], during 1985-86, 135 were interviewed to ascertain the psychosocial factors indluencing their decision to accept MTP [7].

High impact information on MTTP

• A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL [8].
• The microsomal triglyceride transfer protein (MTP), which catalyses the transport of triglyceride, cholesteryl ester and phospholipid between phospholipid surfaces, is a heterodimer composed of the multifunctional protein, protein disulphide isomerase, and a unique large subunit with an apparent M(r) of 88K (refs 1-3) [9].
• This finding suggests that a defect in MTP is the basis for abetalipoproteinemia and that MTP is indeed required for lipoprotein assembly [10].
• The microsomal triglyceride transfer protein (MTP), which is located in the lumen of microsomes isolated from the liver and intestine, has been proposed to function in lipoprotein assembly [10].
• MTP and MTPv1 efficiently transferred phosphatidylethanolamine to CD1d in vitro [11].

Chemical compound and disease context of MTTP

• The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease [12].
• Chronic myeloid leukemia (CML), which is caused by the BCR-ABL fusion tyrosine kinase, is one of the most intensively studied human cancers [13].
• Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia [14].
• In advanced-phase chronic myeloid leukemia (CML), resistance to imatinib mesylate is associated with point mutations in the BCR-ABL kinase domain [15].
• Mutations of helix B (amino acids 781-786) and of N780Y, which causes abetalipoproteinemia, have no impact on the interaction of MTP with phospholipid vesicles but impair triglyceride binding [16].

Biological context of MTTP

• Bile acid reduces the secretion of very low density lipoprotein by repressing microsomal triglyceride transfer protein gene expression mediated by hepatocyte nuclear factor-4 [17].
• PDI binds in close proximity to this apoB binding site on MTP [18].
• Transient transfection analysis of MTP promoter-driven luciferase gene expression showed that the promoter is active in liver and intestinal cells but not in epithelial cells, consistent with endogenous MTP gene expression [19].
• The -493G --> T polymorphism of MTP was associated with BMD in premenopausal women, with the TT genotype being related to increased BMD [20].
• Association of polymorphisms in CYP17A1, MTP, and VLDLR with bone mineral density in community-dwelling Japanese women and men [20].

Anatomical context of MTTP

• Although several recent experiments have revealed the transcriptional regulation of the MTP gene, little has been revealed to date about hepatocyte nuclear factor-4 (HNF-4)-dependent regulation [17].
• When transiently expressed in Cos-1 cells, the Asn780Tyr mutant MTP bound protein disulfide isomerase (PDI) but displayed negligible MTP activity [1].
• Instead a microsomal triglyceride transfer protein, which exists as a complex with protein disulphide isomerase in the endoplasmic reticulum, has been implicated [21].
• Microsomal triglyceride transfer protein is expressed in ovary, testis and kidney, in addition to liver and small intestine [21].
• In contrast, L35 cells, derived as a single cell clone from FAO cells, do not express L-FABP or MTP nor do they assemble and secrete VLDL [3].

Associations of MTTP with chemical compounds

• Microsomal triglyceride transfer protein (MTP) is involved in the transfer of triglycerides, cholesterol esters, and phospholipids to newly synthesized apolipoprotein (apo) B [17].
• Chenodeoxycholic acid, but not a synthetic FXR ligand, attenuated expression of HNF-4, bringing about a further suppression of MTP gene expression [17].
• Persistence of BCR-ABL-positive (bcr-abl(+)) cells or secondary resistance during imatinib therapy frequently occurs [22].
• In this study, we compared the usefulness of combination therapy of bifonazole (Mycospor cream) + 10% urea ointment (Urepearl) (overlapping application group = group I) with occlusive dressing therapy with the same agents (group II) in the treatment of MTTP, and obtained the following results [23].
• Expression of genetically engineered forms of MTP in Cos-1 cells indicates that the C-terminal portion of MTP is necessary for triglyceride-transfer activity [24].
• Serum lathosterol and hepatic cholesterol concentrations, and mRNA expressions of MTTP, CD36, and FABP1 were similar in GS-free and GS patients [25].

Regulatory relationships of MTTP

• Sterol regulatory element-binding protein negatively regulates microsomal triglyceride transfer protein gene transcription [26].

Other interactions of MTTP

• These results indicate that two nuclear receptors, HNF-4 and FXR, are closely involved in MTP gene expression, and the results provide evidence for a novel interaction between bile acids and lipoprotein metabolism [17].
• These results suggest that CYP17A1 and MTP are susceptibility loci for increased BMD in postmenopausal and premenopausal Japanese women, respectively, and that VLDLR constitutes such a locus in Japanese men [20].
• Expression of ABCG5 and ABCG8 mRNA was lower in the diabetic patients (p<0.05) and MTTP expression was increased (p<0.05) [27].
• There was a positive correlation between NPLC1L1 and MTTP mRNA (p<0.01) and a negative correlation between NPC1L1 and ABCG5 mRNA (p<0.001) [27].
• Furthermore, IL-1 and IL-6 significantly decreased MTP mRNA levels in HepG2 cells [28].

Analytical, diagnostic and therapeutic context of MTTP

• The proximity of these binding sites on MTP for PDI and amino acids 512-721 of apoB was evident from studies carried out in a yeast two-hybrid system and by co-immunoprecipitation [18].
• Two variant proteins comprising amino acids 16-297 of intact MTTP, MTTP(N)-Ile128 and MTTP(N)-Thr128, had similar native secondary structure content, as judged by circular dichroism [2].
• Western blots with a microsomal triglyceride transfer protein) (MTP)-specific antiserum demonstrated that the microsomes of the heart contain the 97-kD subunit of MTP (the subunit involved in the transfer of lipids and assembly of lipoproteins) [29].
• Variants of the microsomal triglyceride transfer protein gene are associated with plasma cholesterol levels and body mass index [30].
• Sequence analysis of the 5' flanking region of the gene revealed potential sites which may bind transcriptional factors and control MTP expression [31].

References