Role of Microsomal Triglyceride Transfer Protein (MTP) in Lipid Processing Pathways in Retinal Pigment Epithelium.

Lipid processing in the retinal pigment epithelium (RPE) is important for maintaining the health and function of the neural retina and the RPE itself. One mode of en mass lipid transport from the RPE is apolipoprotein B-containing lipoproteins (Blps), the assembly of which is regulated by microsomal triglyceride transfer protein (MTP). To gain an initial understanding of how the loss of MTP and, thereby, Blp secretion alters other lipid processing pathways in the RPE, we measured the expression of proteins associated with β-oxidation and lipid droplets in mice lacking MTP expression in the RPE (RPEΔMttp) and age-matched controls.

Casz1 and Znf101/Zfp961 differentially regulate apolipoproteins A1 and B, alter plasma lipoproteins, and reduce atherosclerosis.

High apolipoprotein B-containing (apoB-containing) low-density lipoproteins (LDLs) and low apoA1-containing high-density lipoproteins (HDLs) are associated with atherosclerotic cardiovascular diseases. In search of a molecular regulator that could simultaneously and reciprocally control both LDL and HDL levels, we screened a microRNA (miR) library using human hepatoma Huh-7 cells. We identified miR-541-3p that both significantly decreases apoB and increases apoA1 expression by inducing mRNA degradation of 2 different transcription factors, Znf101 and Casz1.

A novel mutation, Ile344Asn, in microsomal triglyceride transfer protein abolishes binding to protein disulfide isomerase.

Microsomal triglyceride transfer protein (MTP) plays crucial roles in the assembly and secretion of apolipoprotein B-containing lipoproteins and loss of function MTP variants are associated with abetalipoproteinemia, a disease characterized by the absence of these lipoproteins. MTP is a heterodimeric protein of two subunits, MTP and protein disulfide isomerase (PDI). In this study, we report a proband with abetalipoproteinemia who was monitored annually for 10 years in her third decade and had very low plasma lipids and undetectable apoB-containing lipoproteins.

The intestine-specific homeobox (ISX) modulates β-carotene-dependent regulation of microsomal triglyceride transfer protein (MTP) in a tissue-specific manner.

Vitamin A is an essential nutrient crucial to ensuring proper mammalian embryonic development. β-Carotene is the most prevalent form of vitamin A in food that, when transferred in its intact form from mother to the developing tissues, can serve as an in situ source of retinoic acid, the active form of vitamin A. We have previously provided evidence that the maternal-fetal transfer of β-carotene across the placenta is mediated by lipoproteins and that β-carotene itself regulates placenta lipoprotein biogenesis by means of its derivatives β-apo-10'-carotenoids and retinoic acid.

ERICH4 is not involved in the assembly and secretion of intestinal lipoproteins.

Background And Aims: The small intestine plays a central role in lipid metabolism, most notably the uptake of dietary fats that are packaged into chylomicrons and secreted into the circulation for utilisation by peripheral tissues. While microsomal triglyceride transfer protein (MTP) is known to play a key role in this pathway, the intracellular assembly, trafficking, and secretion of chylomicrons is incompletely understood.

Methods And Results: Using human transcriptome datasets to find genes co-regulated with MTTP, we identified ERICH4 as a top hit.

FITM2 deficiency results in ER lipid accumulation, ER stress, and reduced apolipoprotein B lipidation and VLDL triglyceride secretion in vitro and in mouse liver.

Objective: Triglycerides (TGs) associate with apolipoprotein B100 (apoB100) to form very low density lipoproteins (VLDLs) in the liver. The repertoire of factors that facilitate this association is incompletely understood. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytosolic lipid droplet (LD) biogenesis in tissues that do not form VLDL.

Pla2g12b drives expansion of triglyceride-rich lipoproteins.

Vertebrates transport hydrophobic triglycerides through the circulatory system by packaging them within amphipathic particles called Triglyceride-Rich Lipoproteins. Yet, it remains largely unknown how triglycerides are loaded onto these particles. Mutations in Phospholipase A2 group 12B (PLA2G12B) are known to disrupt lipoprotein homeostasis, but its mechanistic role in this process remains unclear.

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function.

Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)-containing lipoproteins (Blps) for export.

Bulky hydrophobic side chains in the β1-sandwich of microsomal triglyceride transfer protein are critical for the transfer of both triglycerides and phospholipids.

Hyperlipidemia predisposes individuals to cardiometabolic diseases, the most common cause of global mortality. Microsomal triglyceride transfer protein (MTP) transfers multiple lipids and is essential for the assembly of apolipoprotein B-containing lipoproteins. MTP inhibition lowers plasma lipids but causes lipid retention in the liver and intestine.

FITM2 deficiency results in ER lipid accumulation, ER stress, reduced apolipoprotein B lipidation, and VLDL triglyceride secretion and in mouse liver.

Objectives: Triglyceride (TG) association with apolipoprotein B100 (apoB100) serves to form very low density lipoproteins (VLDL) in the liver. The repertoire of factors that facilitate this association is incompletely defined. FITM2, an integral endoplasmic reticulum (ER) protein, was originally discovered as a factor participating in cytoplasmic lipid droplets (LDs) in tissues that do not form VLDL.

Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function.

Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or to age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (apoB)-containing lipoproteins (Blps) for export.

'A kiss that took my legs away': a rare presentation of Epstein-Barr virus in the older population.

We present the case of a 70-year-old woman presenting with nausea, diarrhoea and a generalised rash. Initial blood tests revealed obstructive deranged liver function tests and low haemoglobin. A haemolysis screen revealed raised reticulocytes, low haptoglobin and a positive direct antiglobulin test.

Missense mutation Q384K in the APOB gene affecting the large lipid transfer module of apoB reduces the secretion of apoB-100 in the liver without reducing the secretion of apoB-48 in the intestine.

Background: Molecular genetic testing of patients with hypobetalipoproteinemia may identify a genetic cause that can form the basis for starting proper therapy. Identifying a genetic cause may also provide novel data on the structure-function relationship of the mutant protein.

Objective: To identify a genetic cause of hypobetalipoproteinemia in a patient with levels of low density lipoprotein cholesterol at the detection limit of 0.

Intracellular tPA-PAI-1 interaction determines VLDL assembly in hepatocytes.

Apolipoprotein B (apoB)-lipoproteins initiate and promote atherosclerotic cardiovascular disease. Plasma tissue plasminogen activator (tPA) activity is negatively associated with atherogenic apoB-lipoprotein cholesterol levels in humans, but the mechanisms are unknown. We found that tPA, partially through the lysine-binding site on its Kringle 2 domain, binds to the N terminus of apoB, blocking the interaction between apoB and microsomal triglyceride transfer protein (MTP) in hepatocytes, thereby reducing very-low-density lipoprotein (VLDL) assembly and plasma apoB-lipoprotein cholesterol levels.

Characterization of lipoproteins in human placenta and fetal circulation as well as gestational changes in lipoprotein assembly and secretion in human and mouse placentas.

In the maternal circulation, apoB-containing low-density lipoproteins (LDL) and apoA1-containing high-density lipoproteins (HDL) transport lipids. The production of lipoproteins in the placenta has been suggested, but the directionality of release has not been resolved. We compared apolipoprotein concentrations and size-exclusion chromatography elution profiles of lipoproteins in maternal/fetal circulations, and in umbilical arteries/veins; identified placental lipoprotein-producing cells; and studied temporal induction of lipoprotein-synthesizing machinery during pregnancy.

A coding variant in the microsomal triglyceride transfer protein reduces both hepatic steatosis and plasma lipids.

Background: Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby reducing serum lipids and apoB at the expense of increasing hepatic steatosis.

Aim: To examine the effects of missense variants in MTTP on hepatic and circulating lipids.

Methods: We analysed the association of MTTP missense variants with metabolic, hepatic and clinical phenotypes in the Penn Medicine Biobank (PMBB; n = 37,960) and the UKBiobank (UKB; n = 451,444).

New CRISPR Technology for Creating Cell Models of Lipoprotein Assembly and Secretion.

Purpose Of Review: This review is aimed at providing an overview of new developments in gene editing technology, including examples of how this technology has been used to develop cell models for studying the effects of gene ablation or missense mutations on lipoprotein assembly and secretion.

Recent Findings: CRISPR/Cas9-mediated gene editing is superior to other technologies because of its ease, sensitivity, and low off-target effects. This technology has been used to study the importance of microsomal triglyceride transfer protein in the assembly and secretion of apolipoprotein B-containing lipoproteins, as well as to establish causal effects of APOB gene missense mutations on lipoprotein assembly and secretion.

Synthesis of Novel MicroRNA-30c Analogs to Reduce Apolipoprotein B Secretion in Human Hepatoma Cells.

Atherosclerosis, a condition characterized by thickening of the arteries due to lipid deposition, is the major contributor to and hallmark of cardiovascular disease. Although great progress has been made in lowering the lipid plaques in patients, the conventional therapies fail to address the needs of those that are intolerant or non-responsive to the treatment. Therefore, additional novel therapeutic approaches are warranted.

ATP-Binding Cassette Transporter Family C Protein 10 Participates in the Synthesis and Efflux of Hexosylceramides in Liver Cells.

In addition to sphingomyelin and ceramide, sugar derivatives of ceramides, hexosylceramides (HexCer) are the major circulating sphingolipids. We have shown that silencing of ABCA1 transmembrane protein function for instance in cases of loss of function of ABCA1 gene results in low levels of HDL as well as a concomitant reduction in plasma HexCer levels. However, proteins involved in hepatic synthesis and egress of HexCer from cells is not well known although ABCA1 seems to be indirectly controlling the HexCer plasma levels by supporting HDL synthesis.

Guidance for the diagnosis and treatment of hypolipidemia disorders.

The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan.

Microsomal triglyceride transfer protein regulates intracellular lipolysis in adipocytes independent of its lipid transfer activity.

Background: The triglyceride (TG) transfer activity of microsomal triglyceride transfer protein (MTP) is essential for lipoprotein assembly in the liver and intestine; however, its function in adipose tissue, which does not assemble lipoproteins, is unknown. Here we have elucidated the function of MTP in adipocytes.

Approach And Results: We demonstrated that MTP is present on lipid droplets in human adipocytes.