Disease relevance of Mttp

• Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis [1].
• In marked contrast to the MTP-deficient model of fatty liver, electron microscopy of lipid-stained liver sections of Apoe(-/-) mice revealed an accumulation of lipid in numerous small, putative ER-derived vesicles and in the cytosol [2].
• Mutations in MTP are a major cause of abetalipoproteinemia [3].
• FAO rat hepatoma cells express L-FABP and MTP and demonstrate the ability to assemble and secrete VLDL [4].
• We constructed a recombinant adenovirus expressing MTP (AdhMTP) and used it to assess the effects of hepatic overexpression of MTP in mice [5].

High impact information on Mttp

• Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B, associates with CD1d in hepatocytes [1].
• These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo [1].
• Edman degradation of MTPv1 isolated from transfected cells revealed three unique residues; however, recombinant MTP and MTPv1 had an equivalent protein disulfide isomerase association, subcellular localization, triglyceride transfer, phospholipid transfer, response to inhibitors, and ability to support apoB secretion [6].
• We identified MTP variant 1 (MTPv1), a novel splice variant of mouse MTP, by polymerase chain reaction and Northern analysis in non-apoB-secreting tissues, including thymocytes and antigen-presenting cells (APCs) [6].
• MTP and MTPv1 efficiently transferred phosphatidylethanolamine to CD1d in vitro [6].

Biological context of Mttp

• All homozygous embryos (Mttp-/-) died during embryonic development [7].
• These observations prompted us to examine the phenotype following intestine-specific Mttp deletion because murine, like human enterocytes, secrete virtually exclusively apoB48 [8].
• We generated mice with conditional Mttp deletion in villus enterocytes (Mttp-IKO), using a tamoxifen-inducible, intestine-specific Cre transgene [8].
• Compensatory increase in hepatic lipogenesis in mice with conditional intestine-specific Mttp deficiency [8].
• The DNA-deduced amino acid sequence indicates that mouse MTP contains 894 amino acids; the mouse protein shows 93, 86, and 83% sequence identity to the hamster, human, and bovine sequences, respectively [3].

Anatomical context of Mttp

• Both the livers of adult Mttp+/- mice and the visceral endoderm of the yolk sacs from Mttp+/- embryos manifested an accumulation of cytosolic fat [7].
• Thus, these results indicate that the concentration of MTP within the endoplasmic reticulum rather than the MTP:apoB ratio is the critical determinant of lipoprotein secretion [9].
• Surprisingly, loss of MTP expression was associated with a nearly complete absence of apoB-100 in hepatic microsomes [10].
• Northern blot analysis indicates that mouse MTP mRNA is expressed at high levels in the small intestine and at substantially lower levels in the liver and that it is not detectable in six other tissues examined [3].
• Microsomal triglyceride transfer protein (MTP) catalyzes the transfer of triglyceride, cholesteryl ester, and phospholipid between membranes [3].

Associations of Mttp with chemical compounds

• Compared with control mice (Mttp+/+), chow-fed Mttp+/- mice had reduced plasma levels of low-density lipoprotein cholesterol and had a 28% reduction in plasma apoB100 levels [7].
• Consistent with that result, hepatic triglyceride accumulation was greater in heterozygous apoB knockout mice than in heterozygous MTP knockout mice [9].
• Addition of actinomycin D blocked this increase and the MTP promoter (-136 to +67) containing a conserved DR1 element was activated by Wy, showing that PPARalpha activates transcription of the gene [11].
• A retinoid X receptor agonist (9-cis-retinoic acid), but not a PPARgamma agonist (rosiglitazone), increased MTP mRNA expression in cultured hepatocytes from both wild type and PPARalpha-null mice [11].
• We studied hepatic MTP activity, the lipoproteins present in the ER lumen, and hepatic lipoprotein secretion 4 hours after administration of a single dose of amineptine (1 mmol/kg), amiodarone (1 mmol/kg), doxycycline (0.25 mmol/kg), tetracycline (0.25 mmol/kg), tianeptine (0.5 mmol/kg), or pirprofen (2 mmol/kg) in mice [12].
• MTP enhances cellular cholesterol esterification by removing cholesteryl esters from their site of synthesis and depositing them into nascent apoB lipoproteins [13].

Physical interactions of Mttp

• Immunohistochemical and biochemical approaches were utilized to compare the expression of microsomal triglyceride transfer protein (MTP) and cellular retinol binding protein II (CRBPII) with the expression of apolipoprotein (apo)B and apoA-I along the entire length of the small intestine in mice [14].

Co-localisations of Mttp

• Morphometric analyses indicated that approximately 17% of the MTP signal colocalized with the TGN38, while 33% of the trans-Golgi marker colocalized with the MTP [15].

Regulatory relationships of Mttp

• In conclusion, PPARalpha activation stimulates hepatic MTP expression via increased transcription of the Mtp gene [11].

Other interactions of Mttp

• A deficiency of microsomal triglyceride transfer protein reduces apolipoprotein B secretion [9].
• In this study, we sought to determine whether PPARalpha activation increases MTP expression and activity [11].
• However, the relative importance of MTP in the two steps of VLDL assembly and the specific role of the LDL receptor still remain unclear [16].
• We therefore analyzed the embryonic expression of apoB, MTP, and alpha-tocopherol transfer protein (alpha-TTP), which have been associated with the assembly and secretion of apoB-containing lipoproteins in the adult liver, at different developmental time points [17].
• On a high-fat diet, the Mttp+/- mice exhibited a marked reduction in total plasma cholesterol levels, compared with those in Mttp+/+ mice [7].

Analytical, diagnostic and therapeutic context of Mttp

• After Cre induction, hepatic Mttp expression was virtually eliminated (as judged by quantitative real-time PCR), hepatic lipoprotein secretion was abolished (as judged by electron microscopy), and LDLs were virtually eliminated from the plasma [18].
• To characterize the ontogeny of MTP expression during embryonic mouse development, we have used in situ hybridization to characterize the pattern of expression [19].
• Concerning the addition of core neutral lipids in the later stages of lipoprotein assembly, cell culture studies show that MTP lipid transfer activity is not required for this to occur for apolipoprotein B-100 containing lipoproteins [20].
• We show MTP RNA and protein in antigen-presenting cells (APCs) by reverse transcription-polymerase chain reaction and by immunoblotting of mouse liver mononuclear cells and mouse and human B cell lines [21].
• NKT cells fail to develop in fetal thymic organ culture (FTOC) treated with MTP antagonists [6].

References