scholarly journals Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice

Hepatology ◽  
2012 ◽  
Vol 55 (5) ◽  
pp. 1356-1368 ◽  
Author(s):  
Irani Khatun ◽  
Sebastian Zeissig ◽  
Jahangir Iqbal ◽  
Minghui Wang ◽  
David Curiel ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Plasma Lipids ◽  
Microsomal Triglyceride Transfer Protein ◽  
Transfer Protein ◽  
Transfer Activity ◽  
Phospholipid Transfer

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.

scholarly journals Microsomal Triglyceride Transfer Protein Inhibition Induces Endoplasmic Reticulum Stress and Increases Gene Transcription via Ire1α/cJun to Enhance Plasma ALT/AST

2013 ◽  
Vol 288 (20) ◽  
pp. 14372-14383 ◽  
Author(s):  
Joby Josekutty ◽  
Jahangir Iqbal ◽  
Takao Iwawaki ◽  
Kenji Kohno ◽  
M. Mahmood Hussain
Keyword(s):  
Endoplasmic Reticulum ◽  
Free Cholesterol ◽  
Plasma Lipids ◽  
Microsomal Triglyceride Transfer Protein ◽  
Major Mechanism ◽  
Protein Inhibition ◽  
Transfer Protein ◽  
Oxidative Stresses ◽  
Triglyceride Rich Lipoprotein ◽  
Response To Stress

Microsomal triglyceride transfer protein (MTP) is a target to reduce plasma lipids because of its indispensable role in triglyceride-rich lipoprotein biosynthesis. MTP inhibition in Western diet fed mice decreased plasma triglycerides/cholesterol, whereas increasing plasma alanine/aspartate aminotransferases (ALT/AST) and hepatic triglycerides/free cholesterol. Free cholesterol accumulated in the endoplasmic reticulum (ER) and mitochondria resulting in ER and oxidative stresses. Mechanistic studies revealed that MTP inhibition increased transcription of the GPT/GOT1 genes through up-regulation of the IRE1α/cJun pathway leading to increased synthesis and release of ALT1/AST1. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism, in response to ER stress, elevating plasma transaminases. Increases in plasma and tissue transaminases might represent a normal response to stress for survival.

Abstract 574: Whole Body and Hepatocyte-specific Deletion of Bmal1 Induces Hyperlipidemia and Enhances Atherosclerosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Xiaoyue Pan ◽  
Mahmood M Hussain
Keyword(s):  
Plasma Lipids ◽  
Microsomal Triglyceride Transfer Protein ◽  
Diurnal Rhythms ◽  
Whole Body ◽  
Over Expression ◽  
Transfer Protein ◽  
High Incidence ◽  
Clock Mutant ◽  
Accumulation Of Lipids ◽  
Specific Deletion

The aberrant accumulation of lipids in the plasma is associated with high incidence of atherosclerosis. Plasma lipids exhibit diurnal variations. Diurnal rhythms are controlled by two major transcription factors, Clock and Bmal1. Previously, we have shown that expression of a Clock mutant protein predisposes mice to hyperlipidemia and atherosclerosis. Here we show that the complete and liver-specific ablation of Bmal1 gene expression in Apoe -/- mice promotes hyperlipidemia and atherosclerosis. We observed that Bmal1 deficiency increases of microsomal triglyceride transfer protein (MTP) expression. Molecular studies indicated that Bmal1 deficiency decreases the expression of small heterodimer partner (SHP), a repressor MTP, to increase MTP expression and hepatic lipoprotein production. The effect of Bmal1 deficiency on MTP can be circumvented by the hepatic over expression of SHP. Over expression of SHP in the liver-specific Bmal1 deficient Apoe -/- mice reduced atherosclerosis and plasma lipids. These studies show that Bmal1 regulates hepatic lipoprotein production by regulating SHP. Deregulation of these circadian regulatory mechanisms and physiologic pathways predisposes mice to hyperlipidemia and atherosclerosis.

Abstract 115: Microrna-30c Reduces Hyperlipidemia and Atherosclerosis by Decreasing Lipid Synthesis and Lipoprotein Secretion

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
James Soh ◽  
Jahangir Iqbal ◽  
Joyce Queiroz ◽  
Carlos Fernandez-Hernando ◽  
M. Mahmood Hussain
Keyword(s):  
Metabolic Disorders ◽  
Plasma Lipids ◽  
De Novo ◽  
Plasma Cholesterol ◽  
Lipid Synthesis ◽  
Microsomal Triglyceride Transfer Protein ◽  
Atherosclerotic Plaques ◽  
Over Expression ◽  
Transfer Protein ◽  
Lipoprotein Secretion

Hyperlipidemia is a risk factor for various cardiovascular and metabolic disorders. Overproduction of lipoproteins, a process critically dependent on microsomal triglyceride transfer protein (MTP), can contribute to hyperlipidemia. We have shown that hepatic over expression of miR-30c reduces MTP mRNA, protein and activity. Further, MTP mRNA is degraded faster due to the binding of miR-30c to its 3[[Unable to Display Character: ΄]]-UTR. miR-30c lowers plasma cholesterol by reducing production of triglyceride-rich apoB-containing lipoproteins; a phenotype most likely secondary to lower MTP expression. It also reduces de novo lipogenesis by targeting other genes such as LPGAT1. Additionally, atherosclerotic plaques are smaller in Apoe -/- mice expressing miR-30c. Taken together, we have provided evidence that high miR-30c levels reduce plasma lipids and atherosclerosis and avoids steatosis by regulating different sets of genes.

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.

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