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The Journal of Nutrition Feb 1999Apolipoprotein (apo) B and the microsomal triglyceride transfer protein are essential for the hepatic assembly and secretion of triglyceride-rich VLDL. To understand how... (Review)
Review
Apolipoprotein (apo) B and the microsomal triglyceride transfer protein are essential for the hepatic assembly and secretion of triglyceride-rich VLDL. To understand how apoB initiates the process of lipoprotein formation, interest has focused on the biogenesis of its amino terminal globular domain (alpha1 domain). When only this domain is expressed in hepatoma cells, no lipoprotein particle will form. However, proper folding of the alpha1 domain is essential for the internal lipophilic regions of apoB to engage in cotranslational lipid recruitment. The essential function of this domain may be related to its capacity to promote a specific physical interaction with the microsomal triglyceride transfer protein, necessary for apoB's proper folding and lipidation. Alternatively, this domain may promote an autonomous lipid recruitment step that nucleates microsomal triglyceride transfer protein-dependent lipid sequestration by apoB. Forms of apoB that fail to initiate particle assembly or forms associated with aberrant underlipidated particles are targeted for intracellular turnover. Two sites of apoB degradation have been identified. In hepatocarcinoma-derived cells, misassembled apoB may undergo progressive reverse translocation from the endoplasmic reticulum lumen to the cytosol, a process that is mechanistically coupled to polyubiquitination and proteasome-mediated degradation on the cytosolic side of the membrane. Alternatively, studies in primary hepatocytes reveal that apoB may undergo sorting to a post-endoplasmic reticulum compartment for presecretory degradation. In either case, the balance between assembly and presecretory degradation of apoB may represent a control point for the production of hepatic VLDL.
Topics: Animals; Apolipoproteins B; Biological Transport; Carrier Proteins; Endoplasmic Reticulum, Rough; Humans; Lipoproteins, VLDL; Liver; Protein Biosynthesis; Triglycerides
PubMed: 10064309
DOI: 10.1093/jn/129.2.456S -
Chemistry and Physics of Lipids 1991Nuclear magnetic resonance spectroscopy has been used to investigate the effect of the lung surfactant apolipoproteins B/C on dipalmitoylphosphatidylcholine to address...
Nuclear magnetic resonance spectroscopy has been used to investigate the effect of the lung surfactant apolipoproteins B/C on dipalmitoylphosphatidylcholine to address the mechanism by which the adsorption rate of phospholipids from the bulk to the air/water interface is enhanced. Apolipoproteins B/C were isolated from bovine lung and separated from associated lipids by lipophilic Sephadex column chromatography. Amino acid analysis indicated the presence of both apolipoproteins B and C. The 13C chemical shift anisotropy of DPPC was determined as a function of temperature. Previous workers (Wittebort et al., Biochemistry, 20 (1981) 3487-3502) have concluded that the observed magnitude of the chemical shift anisotropy of the carbonyl group of the sn-2 acyl chain in pure DPPC is a result of rapid rotation about an axis along the length of the phospholipid both in the gel and liquid crystalline state. The orientation of the carbonyl group with respect to the axis of diffusion, however, undergoes an approximately 25-30 degrees shift in passage from the gel to liquid crystalline state, with the intermediate, rippled (P beta') state composed of an exchange between these two orientations. The presence of physiological concentrations SP-B/C reduced the width of the anisotropy of DPPC below but had no effect on lipids above the main phase transition temperature. This suggests that SP-B/C has a general effect on the entire assembly of lipids. The temperature of the onset of the orientational change is lowered indicating a portion of the lipids are affected by the lung surfactant apolipoproteins.
Topics: 1,2-Dipalmitoylphosphatidylcholine; Animals; Apolipoproteins B; Apolipoproteins C; Carbon Isotopes; Cattle; Female; Magnetic Resonance Spectroscopy; Pulmonary Surfactants; Temperature; Therapeutic Irrigation; Thermodynamics
PubMed: 1934195
DOI: 10.1016/0009-3084(91)90111-n -
Current Atherosclerosis Reports Jan 2010As new studies demonstrate that lower levels of low-density lipoprotein cholesterol (LDL-C) reduce cardiovascular disease, and as goals for LDL-C in high-risk... (Review)
Review
As new studies demonstrate that lower levels of low-density lipoprotein cholesterol (LDL-C) reduce cardiovascular disease, and as goals for LDL-C in high-risk individuals are reduced further and further, reaching those goals becomes more difficult for a significant percentage of the population. New therapeutic approaches to lower LDL-C would, therefore, be advantageous, particularly in those who are most likely to suffer cardiovascular disease-associated morbidity and mortality. Mouse and human genetic models suggest that decreasing hepatic apolipoprotein B (apoB) production may be a therapeutic approach for the treatment of dyslipidemia. Because antisense oligonucleotides naturally distribute to the liver and can specifically inhibit synthesis of proteins from their messenger RNAs, antisense oligonucleotides represent a potential approach for decreasing the biosynthesis of apoB, and thereby, the production of both very low density lipoprotein (VLDL) and LDL. Newly developed apoB antisense approaches have produced results in animal models and humans, providing proof of concept regarding reductions in LDL-C concentrations. Surprisingly, despite prior experience with inhibitors of microsomal triglyceride transfer protein, which also inhibits the secretion of VLDL, apoB antisense-mediated reduction in VLDL secretion does not appear to cause marked steatosis. The mechanisms whereby two different approaches for inhibiting apoB and triglyceride secretion have different effects on hepatic triglycerides are currently being examined.
Topics: Animals; Apolipoproteins B; Drug Design; Humans; Hyperlipidemias; Hypolipidemic Agents; Liver; Oligonucleotides
PubMed: 20425272
DOI: 10.1007/s11883-009-0078-7 -
Experimental Cell Research Oct 2003Apolipoprotein B is a large, amphipathic protein that plays a central role in lipoprotein metabolism. Because its overproduction and deficiency leads to metabolic and... (Review)
Review
Apolipoprotein B is a large, amphipathic protein that plays a central role in lipoprotein metabolism. Because its overproduction and deficiency leads to metabolic and pathologic disorders, much effort has been paid to investigate the mechanisms of how its homeostasis is achieved. Earlier and recent studies have showed that apoB gene locus might reside in different chromatin domains in the hepatic and intestinal cells, and two sets of very distinct regulatory elements operate to control its transcription. Posttranscriptional modification of apoB mRNA is performed by a multicomponent enzyme complex, several possible pathways regulate the editing efficiency. Understanding of the mechanism responsible for apoB mRNA editing will provide the basis for C-to-U editing in gene therapy. In addition to apoB mRNA abundance and stability, its translation can be also regulated at the steps of elongation. The translocation of apoB into the ER is an important and complicated process that is less understood. Successful transport and correct folding of apoB may lead to its final secretion, otherwise subject to intracellular degradation, which is accomplished by proteasomal and nonproteasomal pathways at multiple levels and may differ among cell types.
Topics: Animals; Apolipoproteins B; Gene Expression Regulation; Humans; Intestinal Mucosa; Intestines; Liver; Protein Biosynthesis; Protein Transport; RNA Editing; RNA, Messenger
PubMed: 14516783
DOI: 10.1016/s0014-4827(03)00313-6 -
Journal of Lipid Research Jul 2018A better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. apoB-containing lipoproteins (B-lps) are... (Review)
Review
A better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. apoB-containing lipoproteins (B-lps) are macromolecular lipid and protein micelles that act as specialized transport vehicles for hydrophobic lipids. They are assembled predominantly in enterocytes and hepatocytes to transport dietary and endogenous fat, respectively, to different tissues. Assembly occurs in the endoplasmic reticulum (ER) and is dependent on lipid resynthesis in the ER and on a chaperone, namely, microsomal triglyceride transfer protein (MTTP). Precursors for lipid synthesis are obtained from extracellular sources and from cytoplasmic lipid droplets. MTTP is the major and essential lipid transfer protein that transfers phospholipids and triacylglycerols to nascent apoB for the assembly of lipoproteins. Assembly is aided by cell death-inducing DFF45-like effector B and by phospholipid transfer protein, which may facilitate additional deposition of triacylglycerols and phospholipids, respectively, to apoB. Here, we summarize the current understanding of the different steps in the assembly of B-lps and discuss the role of lipid transfer proteins in these steps to help identify new clinical targets for lipid-associated disorders, such as heart disease.
Topics: Animals; Apolipoproteins B; Carrier Proteins; Humans
PubMed: 29650752
DOI: 10.1194/jlr.R083451 -
Current Opinion in Lipidology Oct 2016Today, it is no longer a hypothesis, but an established fact, that increased plasma concentrations of cholesterol-rich apolipoprotein-B (apoB)-containing lipoproteins... (Review)
Review
PURPOSE OF REVIEW
Today, it is no longer a hypothesis, but an established fact, that increased plasma concentrations of cholesterol-rich apolipoprotein-B (apoB)-containing lipoproteins are causatively linked to atherosclerotic cardiovascular disease (ASCVD) and that lowering plasma LDL concentrations reduces cardiovascular events in humans. Here, we review evidence behind this assertion, with an emphasis on recent studies supporting the 'response-to-retention' model - namely, that the key initiating event in atherogenesis is the retention, or trapping, of cholesterol-rich apoB-containing lipoproteins within the arterial wall.
RECENT FINDINGS
New clinical trials have shown that ezetimibe and anti-PCSK9 antibodies - both nonstatins - lower ASCVD events, and they do so to the same extent as would be expected from comparable plasma LDL lowering by a statin. These studies demonstrate beyond any doubt the causal role of apoB-containing lipoproteins in atherogenesis. In addition, recent laboratory experimentation and human Mendelian randomization studies have revealed novel information about the critical role of apoB-containing lipoproteins in atherogenesis. New information has also emerged on mechanisms for the accumulation in plasma of harmful cholesterol-rich and triglyceride-rich apoB-containing remnant lipoproteins in states of overnutrition. Like LDL, these harmful cholesterol-rich and triglyceride-rich apoB-containing remnant lipoprotein remnants become retained and modified within the arterial wall, causing atherosclerosis.
SUMMARY
LDL and other cholesterol-rich, apoB-containing lipoproteins, once they become retained and modified within the arterial wall, cause atherosclerosis. This simple, robust pathophysiologic understanding may finally allow us to eradicate ASCVD, the leading killer in the world.
Topics: Animals; Apolipoproteins B; Arteries; Atherosclerosis; Cholesterol; Humans; Protein Aggregates; Risk Factors
PubMed: 27472409
DOI: 10.1097/MOL.0000000000000330 -
Nature Communications Jul 2022Lipid metabolism plays an instructive role in regulating stem cell state and differentiation. However, the roles of lipid mobilization and utilization in stem...
Lipid metabolism plays an instructive role in regulating stem cell state and differentiation. However, the roles of lipid mobilization and utilization in stem cell-driven regeneration are unclear. Planarian flatworms readily restore missing tissue due to injury-induced activation of pluripotent somatic stem cells called neoblasts. Here, we identify two intestine-enriched orthologs of apolipoprotein b, apob-1 and apob-2, which mediate transport of neutral lipid stores from the intestine to target tissues including neoblasts, and are required for tissue homeostasis and regeneration. Inhibition of apob function by RNAi causes head regression and lysis in uninjured animals, and delays body axis re-establishment and regeneration of multiple organs in amputated fragments. Furthermore, apob RNAi causes expansion of the population of differentiating neoblast progeny and dysregulates expression of genes enriched in differentiating and mature cells in eight major cell type lineages. We conclude that intestine-derived lipids serve as a source of metabolites required for neoblast progeny differentiation.
Topics: Animals; Apolipoproteins; Apolipoproteins B; Intestines; Planarians; Pluripotent Stem Cells
PubMed: 35778403
DOI: 10.1038/s41467-022-31385-2 -
Biochimica Et Biophysica Acta Nov 2000RNA editing is a post-transcriptional process that changes the informational capacity within the RNA. These processes include alterations made by nucleotide deletion,... (Review)
Review
RNA editing is a post-transcriptional process that changes the informational capacity within the RNA. These processes include alterations made by nucleotide deletion, insertion and base conversion. A to I and C to U conversion occurs in mammals and these editing events are catalysed by RNA binding deaminases. C to U editing of apoB mRNA was the first mammalian editing event to be identified. The minimal protein complex necessary for apoB mRNA editing has been determined and consists of APOBEC-1 and ACF. Overexpression of APOBEC-1 in transgenic animals caused liver dysplasia and APOBEC-1 has been identified in neurofibromatosis type 1 tumours, suggesting that RNA editing may be another mechanism for tumourigenesis. Several APOBEC-1-like proteins have been identified, including a family of APOBEC-1-related proteins with unknown function on chromosome 22. This review summarises the different types of RNA editing and discusses the current status of C to U apoB mRNA editing. This knowledge is very important in understanding the structure and function of these related proteins and their role in biology.
Topics: APOBEC-1 Deaminase; Animals; Apolipoproteins B; Base Sequence; Catalytic Domain; Cytidine; Cytidine Deaminase; Genetic Therapy; Humans; Models, Molecular; Molecular Sequence Data; Neoplasms; Phylogeny; RNA Editing; RNA, Messenger; Sequence Alignment; Uridine
PubMed: 11072063
DOI: 10.1016/s0167-4781(00)00219-0 -
The Journal of Nutrition Feb 1999The liver plays a primary role in lipid metabolism. Important functions include the synthesis and incorporation of hydrophobic lipids, triacylglycerols and cholesteryl... (Review)
Review
The liver plays a primary role in lipid metabolism. Important functions include the synthesis and incorporation of hydrophobic lipids, triacylglycerols and cholesteryl esters into the core of water-miscible particles called lipoproteins and the secretion of these particles into the circulation for transport to distant tissues. In this article, we present a brief overview of one aspect of the assembly process of very low density lipoproteins, namely, possible mechanisms for combining core lipids with apolipoprotein B. This is a complex process in which apolipoprotein B interacts with core lipids to form very low density lipoproteins by a two-step process that can be dissociated biochemically.
Topics: Animals; Apolipoprotein B-48; Apolipoproteins B; Brefeldin A; Carrier Proteins; Humans; Lipid Metabolism; Lipoproteins, VLDL; Microsomes, Liver; Protein Synthesis Inhibitors
PubMed: 10064310
DOI: 10.1093/jn/129.2.463S -
Cold Spring Harbor Perspectives in... Jun 2023APOB-containing lipoproteins are large, complex lipid carriers that ferry bulk lipids into the circulation via the secretory pathway, originating from the endoplasmic... (Review)
Review
APOB-containing lipoproteins are large, complex lipid carriers that ferry bulk lipids into the circulation via the secretory pathway, originating from the endoplasmic reticulum of specialized cells in the liver or the gut. Elevation of APOB-containing lipoproteins in the plasma represents a major risk factor for cardiovascular diseases. The production of these lipoproteins requires enzyme-catalyzed, cross-membrane transfer of neutral lipids and phospholipids to lipoproteins, in particular onto the structural component APOB. Transport of these lipid-bearing cargos relies on the COPII machinery and employs the transmembrane cargo receptor SURF4 and the small GTPase SAR1B, together constituting a selective transport program. Intriguingly, a number of factors implicated in lipoprotein production are also packaged into COPII vesicles and may be cotransported with APOB. These observations therefore point to a specialized produce-and-export itinerary during the secretion of these lipid-bearing cargos, warranting future investigations into this unique yet pivotal process at the crossroad of cell biology and physiology.
Topics: Carrier Proteins; Lipoproteins; Endoplasmic Reticulum; Apolipoproteins B; Homeostasis; Protein Transport; COP-Coated Vesicles
PubMed: 36096639
DOI: 10.1101/cshperspect.a041260