scholarly journals A missense mutation dissociates triglyceride and phospholipid transfer activities in zebrafish and human microsomal triglyceride transfer protein

2019 ◽  
Author(s):  
Meredith H. Wilson ◽  
Sujith Rajan ◽  
Aidan Danoff ◽  
Richard J. White ◽  
Monica R. Hensley ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Apolipoprotein B ◽  
Lipid Droplets ◽  
Transfer Functions ◽  
Microsomal Triglyceride Transfer Protein ◽  
Normal Growth ◽  
Selective Inhibition ◽  
Transfer Protein ◽  
Transfer Activity ◽  
Phospholipid Transfer

SUMMARYMicrosomal triglyceride transfer protein (MTP) transfers triglycerides and phospholipids and is essential for the assembly of Apolipoprotein B (ApoB)-containing lipoproteins in the endoplasmic reticulum. We have discovered a zebrafish mutant (mttpc655) expressing a C-terminal missense mutation (G863V) in Mttp, one of the two subunits of MTP, that is defective at transferring triglycerides, but retains phospholipid transfer activity. Mutagenesis of the conserved glycine in the human MTTP protein (G865V) also eliminates triglyceride but not phospholipid transfer activity. The G863V mutation reduces the production and size of ApoB-containing lipoproteins in zebrafish embryos and results in the accumulation of cytoplasmic lipid droplets in the yolk syncytial layer. However, mttpc655 mutants exhibit only mild intestinal lipid malabsorption and normal growth as adults. In contrast, zebrafish mutants bearing the previously identified mttpstl mutation (L475P) are deficient in transferring both triglycerides and phospholipids and exhibit gross intestinal lipid accumulation and defective growth. Thus, the G863V point mutation provides the first evidence that the triglyceride and phospholipid transfer functions of a vertebrate MTP protein can be separated, arguing that selective inhibition of the triglyceride transfer activity of MTP may be a feasible therapeutic approach for dyslipidemia.

Abstract 232: A Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal ß-Sheet in the Lipid Transfer and ApoB Secretion Activities of Microsomal Triglyceride Transfer Protein

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Meghan T Walsh ◽  
Enza Di Leo ◽  
Eda Ozaydin ◽  
Patrizia Tarugi ◽  
Mahmood Hussain
Keyword(s):  
Missense Mutation ◽  
Structural Integrity ◽  
Microsomal Triglyceride Transfer Protein ◽  
Salt Bridge ◽  
Missense Mutations ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Transfer Activity ◽  
Apob Secretion ◽  
Β Sheet

Microsomal triglyceride transfer protein (MTP) is critical for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins. Mutations in the MTTP gene cause abetalipoproteinemia (ABL). Missense mutations in ABL have revealed that the central α-helical and C-terminal β-sheet domains are important for the lipid transfer activity of MTP and for the assembly and secretion of apoB-containing lipoproteins. The N-terminal domain, on the other hand, has mainly been implicated in apoB- and membrane-binding. Here, we describe a novel ABL missense mutation (D169V) in the N-terminal β-sheet of MTP. Although this mutant MTP (MTPD169V) is expressed and localized to the endoplasmic reticulum, it is unable to transfer triglycerides and phospholipids. Further, MTPD169V does not support the assembly and secretion of apoB-containing lipoproteins. Computational molecular modeling suggests that D169 could form an internal salt bridge with K187 and K189. Indeed, mutagenesis of these lysine residues to leucine abolishes triglyceride transfer and apoB secretion activities of MTP. Furthermore, conservative mutagenesis that preserves charges on these residues partially restores triglyceride transfer and apoB secretion activities of MTP. Therefore, D169 is probably involved in an internal salt bridge with K187 and K189. Disruption of this internal salt bridge in the N-terminal region affects the lipid transfer activity present in the C-terminal end of the MTP molecule. We speculate that this salt bridge, although away from the speculated lipid transfer site, might be important in providing structural integrity necessary for the lipid transfer activity of MTP.

scholarly journals Elevated Phospholipid Transfer Protein in Subjects with Multiple Sclerosis

2015 ◽  
Vol 2015 ◽  
pp. 1-5
Author(s):  
Roy A. Garvin
Keyword(s):  
Multiple Sclerosis ◽  
Structural Changes ◽  
Protein A ◽  
High Density Lipoproteins ◽  
Phospholipid Transfer Protein ◽  
Lipid Uptake ◽  
Myelin Lipid ◽  
Transfer Protein ◽  
Transfer Activity ◽  
Phospholipid Transfer

An anomaly in the plasma proteins of patients with multiple sclerosis detectable on SDS-PAGE has been reported. The molecular weight of the anomaly was the same as the phospholipid transfer protein. A metabolic protein was involved in lipid homeostasis and remodeling of the high density lipoproteins. We have identified the anomaly as the phospholipid transfer protein by western blot using antiphospholipid transfer antibodies. Activity assays showed that the phospholipid transfer activity was elevated in fasted plasma samples from subjects with MS compared to controls. Sequence analysis of the gene encoding the phospholipid transfer protein did not identify any mutations in the genetic structure, suggesting that the increase in activity was not due to structural changes in the protein, but may be due to one of the other proteins with which it forms active complexes. Altered phospholipid transfer activity is important because it could be implicated in the decreased lipid uptake and abnormal myelin lipids observed in multiple sclerosis. It has been shown that alteration in myelin lipid content is an epitope for autoimmunity. Therefore, lipid changes due to a defect in phospholipid transfer and/or uptake could potentially influence the course of the disease. Further research is needed to elucidate the role of the phospholipid transfer protein in subjects with multiple sclerosis.

Development and Physiological Regulation of Intestinal Lipid Absorption. I. Development of intestinal lipid absorption: cellular events in chylomicron assembly and secretion

2007 ◽  
Vol 293 (3) ◽  
pp. G519-G524 ◽  
Author(s):  
Dennis D. Black
Keyword(s):  
Dietary Fat ◽  
Apolipoprotein B ◽  
Microsomal Triglyceride Transfer Protein ◽  
Lipid Absorption ◽  
Cellular Mechanisms ◽  
Peripheral Tissues ◽  
Physiological Regulation ◽  
Transfer Protein ◽  
Cellular Events ◽  
Apolipoprotein A

The newborn mammal must efficiently absorb dietary fat, predominantly as triacylglycerol, and produce chylomicrons to deliver this lipid to peripheral tissues. The cellular mechanisms involved in enterocyte chylomicron assembly have recently been elucidated, and data on their regulation in the immature gut are beginning to emerge. This review focuses on key proteins involved in chylomicron assembly: apolipoprotein B-48, microsomal triglyceride transfer protein, and apolipoproten A-IV. Recent studies support a role for apolipoprotein A-IV in enhancing chylomicron secretion by promoting production of larger particles. These proteins are regulated in a manner to maximize the lipid absorptive capacity of the newborn intestine.

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