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Molecular BioSystems Sep 2007Triglycerides are insoluble in water and yet are transported at milligram per millilitre concentrations in the bloodstream. This is made possible by the ability of the... (Review)
Review
Triglycerides are insoluble in water and yet are transported at milligram per millilitre concentrations in the bloodstream. This is made possible by the ability of the liver and intestine to assemble lipid-protein emulsions (i.e. lipoproteins), which transport hydrophobic molecules. The assembly of triglyceride-rich lipoproteins requires the coordination of protein and lipid synthesis, which occurs on the cytoplasmic surface of the endoplasmic reticulum (ER), and their concerted assembly and translocation into the luminal ER secretory pathway as nascent lipoprotein particles. The availability of lipid substrate for triglyceride production and the machinery for lipoprotein assembly are highly sensitive to nutritional, hormonal, and genetic modulation. Disorders in lipid metabolism or an imbalance between lipogenesis and lipoprotein assembly can lead to hyperlipidemia and/or hepatic steatosis. We selectively review recently-identified machinery, such as transcription factors and nuclear hormone receptors, which provide new clues to the regulation of lipoprotein secretion.
Topics: Animals; Apolipoproteins B; Diabetes Mellitus; Humans; Insulin Resistance; Lipoproteins; Protein Structure, Quaternary; Receptors, LDL
PubMed: 17700861
DOI: 10.1039/b700706j -
Diabetologia Dec 2023This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes...
AIMS/HYPOTHESIS
This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk.
METHODS
To investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL.
RESULTS
The fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL and VLDL density ranges (all p < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 ± 57 vs 446 ± 57 mg/day; p < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 ± 25 vs 82 ± 58 pools/day; p=0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 ± 2.2 vs 1.0 ± 1.8 pools/day; p < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation (p < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL.
CONCLUSIONS/INTERPRETATION
Abnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in individuals with type 2 diabetes on statins may help to explain the residual risk of CVD and may be suitable targets for interventions.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02948777.
Topics: Humans; Apolipoprotein B-100; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Apolipoprotein B-48; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Lipoproteins, VLDL; Apolipoproteins B; Lipoproteins; Triglycerides; Lipoproteins, IDL; Chylomicrons
PubMed: 37775612
DOI: 10.1007/s00125-023-06008-0 -
Nucleic Acids Research Aug 1988
Topics: Amino Acid Sequence; Animals; Apolipoproteins B; Base Sequence; Genes; Molecular Sequence Data; Nucleic Acid Hybridization; Rabbits
PubMed: 3419914
DOI: 10.1093/nar/16.16.8187 -
Clinical Biochemistry Nov 2014Numerous publications have shown strong association between CHD risk and either apolipoprotein B (Apo-B) or low density lipoprotein (LDL) particle number (LDL-P). It is...
OBJECTIVES
Numerous publications have shown strong association between CHD risk and either apolipoprotein B (Apo-B) or low density lipoprotein (LDL) particle number (LDL-P). It is however unknown if Apo-B or LDL-P has a stronger predictive ability for future CHD. This uncertainty may be due to the inability of current Apo-B assays to separate the contribution of very low-density lipoprotein particles from the total Apo-B concentration. As such we have performed a laboratory validation of the Maine Standards LDL Apo-B assay on the Roche Cobas 6000 analyzer.
DESIGN AND METHODS
Imprecision, linear range, and limit of quantitation studies were performed using quality control materials. Plasma samples collected for lipid profile analysis were analyzed via the LDL Apo-B assay and compared to the LDL cholesterol (LDL-C) concentration determined via direct LDL assay and Friedewald equation.
RESULTS
The LDL Apo-B within-run imprecision was 2.3% at 62 mg/dL and 2.2% at 109 mg/dL. The within-laboratory imprecision was 9.7% at 57 mg/dl and 6.1% at 104 mg/dL. Linear regression analysis of LDL Apo-B versus calculated and measured LDL-c resulted in equations of LDL Apo-B=0.620∗(LDL)+45.4, R=0.9063 and LDL-Apo-B=0.607∗(LDL)+38.8, R=0.9393, respectively. Bias plot analyses revealed that at low LDL-C concentration, there was a tendency for a higher than anticipated LDL Apo-B concentration.
CONCLUSIONS
The Maine Standards LDL Apo-B assay is a precise automated assay and comparison of LDL Apo-B to LDL-c concentration demonstrates that low LDL-C concentrations may still carry residual risk of CHD due to increased concentration of small dense LDL particles.
Topics: Apolipoproteins B; Biological Assay; Lipoproteins, LDL
PubMed: 25079242
DOI: 10.1016/j.clinbiochem.2014.07.016 -
American Heart Journal Feb 1987Apolipoprotein (apo) B100 copy deoxyribonucleic acid (cDNA) has been cloned and sequenced. The total sequence of apo B100 messenger ribonucleic acid has been revealed by...
Apolipoprotein (apo) B100 copy deoxyribonucleic acid (cDNA) has been cloned and sequenced. The total sequence of apo B100 messenger ribonucleic acid has been revealed by the work from our group, as well as other groups. The sequence spans 13,689 nucleotides from the initiation to the stop codon. Thus the messenger has the capacity to code for 4563 amino acids corresponding to a molecular weight of approximately 510,000. Computer analyses revealed the presence of regions with amphipathic alpha-helix and of hydrophobic regions with a high probability of beta-structure. Regions of the molecule are characterized by continuous variations between hydrophillic and hydrophobic sequences, the latter coinciding with a high probability of beta-structure. It is suggested that this beta-structure is involved, together with the amphipathic alpha-helix, in the binding of apo B100 to the lipid. Pulse-chase studies in Hep G2 cells showed that apo B100 is synthesized as one protein, with a translation time of 14 minutes. The protein is transferred through the cell and secreted within 30 minutes without undergoing any major change in molecular mass. The residence kinetics in the endoplasmic reticulum (ER) is characterized by an increase during the first 10 to 15 minutes of chase followed by an almost linear decrease with a decay rate of 6%/min. The transfer through the ER to the Golgi apparatus accounts for one third of the time needed for the intracellular transfer of apo B100, whereas two thirds of the time is required for the transfer through the later part of the secretory pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Amino Acid Sequence; Apolipoproteins B; Base Sequence; Biological Transport; Cell Line; Cloning, Molecular; DNA; Humans; RNA, Messenger
PubMed: 3812204
DOI: 10.1016/0002-8703(87)90612-0 -
The Journal of Clinical Investigation Nov 1990Our laboratory has previously shown that insulin inhibits the secretion of newly-synthesized and immunoreactive apo B from rat hepatocytes. We have also shown that apo B...
Our laboratory has previously shown that insulin inhibits the secretion of newly-synthesized and immunoreactive apo B from rat hepatocytes. We have also shown that apo B is secreted as a phosphoprotein and that phosphorylation is increased in hypoinsulinemic nonketotic diabetes. The present studies were conducted to determine whether the ability of insulin to inhibit apo B secretion is related to alterations in apo B turnover and whether insulin itself affects apo B phosphorylation. Pulse-chase studies with [35S]methionine in primary cultures of hepatocytes from normal rats in the absence and presence of insulin show that the secretion of apo B100 and apo B48 are inhibited by insulin and that this inhibition may be due in part to enhanced intracellular degradation. In addition, there is a second intracellular apo B48 pool which is not insulin regulated or degraded. In experiments in which hepatocytes were incubated with [32P]orthophosphate, insulin decreased 32P incorporation into apo B100 (42%) with only small effects on apo B48 (11%). The small insulin effect on apo B48 may relate to an insulin-insensitive apo B48 intracellular pool. These studies show that insulin can affect the intracellular turnover, secretion, degradation, and phosphorylation of apo B and emphasize the differential regulation of apo B100 and apo B48 with regard to these parameters in rat liver.
Topics: Animals; Apolipoprotein B-100; Apolipoprotein B-48; Apolipoproteins B; Cells, Cultured; Insulin; Liver; Male; Phosphorylation; Rats; Rats, Inbred Strains
PubMed: 2243143
DOI: 10.1172/JCI114900 -
Biokhimiia (Moscow, Russia) Jan 1996Based on the model of an oil drop of the apolipoprotein B-100 lipoproteins (apo-B-100 LP) structure and physico-chemical and antigenic differences in their individual... (Review)
Review
Based on the model of an oil drop of the apolipoprotein B-100 lipoproteins (apo-B-100 LP) structure and physico-chemical and antigenic differences in their individual classes, an alternative model has been developed. If the apo-B-100 contains one hydrophilic ligand domain, two hydrophobic domains with predominating alpha-structures and two domains with predominating beta-folding, the molecule may acquire the conformation of a disc, one side of which is hydrophilic, while the other one is hydrophobic. The hydrophilic side of the disc comprises the ligand domain; on the hydrophobic side apo-B-100 forms nonpolar lipids. Apo-B-100 LP has the structure of a bilayer protein-lipid disc. Stepwise alterations in the apo-B-100 disc configuration during lipolysis determine the conversion of apo-B-100 LP in the blood flow: very low density LP-->low density LP. Conformational changes in the apo-B-100 disc form the basis for antigenic differences in each class of LP. Changes in the conformation of apo-B-100 disc in LP induce lipolysis and the formation of cholesterol esters circulating in the functional cycle, in which the cell is the indispensable step. The functional turnover of cholesterol in tissues integrates into one cycle lipoproteins of both high and low density. Equimolar substitution of triglycerides for more hydrophobic cholesterol esters associated with the C-terminal domain of apo-B-100 receptor of the cell. During triglyceride transport the apo-B-100 disc consecutively acquires three configurations--initial, intermediate and final. This hypothesis made the basis for functional classification of apo-B-100 LP in which the initial, intermediate and final classes can be singled out. Blockade of the functional cycle of cholesterol at various stages gives rise to individual hyperlipoproteinemia phenotypes. LP of one class only are accumulated in the blood for each type: the initial class in type III, the intermediate class in type IIb and the final class in type IIa. Each of the three apo-B-100 LP classes is distinguished for its peculiar structure and significant differences in the mechanism of their reception by the cells.
Topics: Apolipoprotein B-100; Apolipoproteins B; Humans; Lipoproteins, LDL; Protein Conformation; Structure-Activity Relationship
PubMed: 8679776
DOI: No ID Found -
Current Opinion in Lipidology Oct 2000The pathogenesis for atherosclerosis is still unclear, and several hypotheses have been articulated to explain the initiating events in atherogenesis. Although these... (Review)
Review
The pathogenesis for atherosclerosis is still unclear, and several hypotheses have been articulated to explain the initiating events in atherogenesis. Although these hypotheses are by no means mutually exclusive, there is a growing body of recent evidence that has led to the concept that subendothelial retention of apolipoprotein B100-containing lipoproteins is the initiating event in atherogenesis. Subsequently, a series of biological responses to this retained material leads to specific molecular and cellular processes that promote lesion formation. The present review assesses some of the studies that support this concept.
Topics: Animals; Apolipoprotein B-100; Apolipoprotein B-48; Apolipoproteins B; Arteriosclerosis; Extracellular Matrix; Glycosaminoglycans; Humans; Lipoproteins, LDL; Models, Cardiovascular; Protein Binding; Proteoglycans
PubMed: 11048887
DOI: 10.1097/00041433-200010000-00002 -
Biochemical Pharmacology Apr 2017Host defence peptides (HDPs) are short, cationic amphipathic peptides that play a key role in the response to infection and inflammation in all complex life forms. It is...
Host defence peptides (HDPs) are short, cationic amphipathic peptides that play a key role in the response to infection and inflammation in all complex life forms. It is increasingly emerging that HDPs generally have a modest direct activity against a broad range of microorganisms, and that their anti-infective properties are mainly due to their ability to modulate the immune response. Here, we report the recombinant production and characterization of two novel HDPs identified in human Apolipoprotein B (residues 887-922) by using a bioinformatics method recently developed by our group. We focused our attention on two variants of the identified HDP, here named r(P)ApoB and r(P)ApoB, 38- and 26-residue long, respectively. Both HDPs were found to be endowed with a broad-spectrum antimicrobial activity while they show neither toxic nor haemolytic effects towards eukaryotic cells. Interestingly, both HDPs were found to display a significant anti-biofilm activity, and to act in synergy with either commonly used antibiotics or EDTA. The latter was selected for its ability to affect bacterial outer membrane permeability, and to sensitize bacteria to several antibiotics. Circular dichroism analyses showed that SDS, TFE, and LPS significantly alter r(P)ApoB conformation, whereas slighter or no significant effects were detected in the case of r(P)ApoB peptide. Interestingly, both ApoB derived peptides were found to elicit anti-inflammatory effects, being able to mitigate the production of pro-inflammatory interleukin-6 and nitric oxide in LPS induced murine macrophages. It should also be emphasized that r(P)ApoB peptide was found to play a role in human keratinocytes wound closure in vitro. Altogether, these findings open interesting perspectives on the therapeutic use of the herein identified HDPs.
Topics: 3T3 Cells; Animals; Apolipoproteins B; Circular Dichroism; HeLa Cells; Humans; Mice; Peptide Fragments; Protein Structure, Secondary; Recombinant Proteins; Spectrophotometry, Ultraviolet
PubMed: 28131846
DOI: 10.1016/j.bcp.2017.01.009 -
Biochimica Et Biophysica Acta Apr 2006Substantial evidence supports the notion that oxidative processes contribute to the pathogenesis of atherosclerosis and coronary heart disease. The nature of the... (Review)
Review
Substantial evidence supports the notion that oxidative processes contribute to the pathogenesis of atherosclerosis and coronary heart disease. The nature of the oxidants that give rise to the elevated levels of oxidised lipids and proteins, and decreased levels of antioxidants, detected in human atherosclerotic lesions are, however, unclear, with multiple species having been invoked. Over the last few years, considerable data have been obtained in support of the hypothesis that oxidants generated by the heme enzyme myeloperoxidase play a key role in oxidation reactions in the artery wall. In this article, the evidence for a role of myeloperoxidase, and oxidants generated therefrom, in the modification of low-density lipoprotein, the major source of lipids in atherosclerotic lesions, is reviewed. Particular emphasis is placed on the reactions of the reactive species generated by this enzyme, the mechanisms and sites of damage, the role of modification of the different components of low-density lipoprotein, and the biological consequences of such oxidation on cell types present in the artery wall and in the circulation, respectively.
Topics: Animals; Apolipoprotein B-100; Apolipoproteins B; Atherosclerosis; Humans; Hypochlorous Acid; Lipid Peroxidation; Lipoproteins, LDL; Oxidants; Oxidation-Reduction; Peroxidase
PubMed: 16698314
DOI: 10.1016/j.bbalip.2006.03.024