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Nature Mar 1992
Topics: Apolipoproteins B; Biological Transport; Endoplasmic Reticulum; Protein Processing, Post-Translational
PubMed: 1545861
DOI: 10.1038/356115b0 -
Frontiers of Hormone Research 1999
Review
Topics: APOBEC-1 Deaminase; Amino Acid Sequence; Animals; Apolipoproteins B; Binding Sites; Cytidine Deaminase; Humans; Molecular Sequence Data; Molecular Structure; Neoplasms; RNA Editing; RNA, Messenger
PubMed: 10941404
DOI: 10.1159/000060998 -
Current Opinion in Lipidology Jun 2005Apolipoprotein B-containing lipoprotein assembly and secretion is critical for lipid absorption and triglyceride homeostasis, and plays a role in atherogenesis and the... (Review)
Review
PURPOSE OF REVIEW
Apolipoprotein B-containing lipoprotein assembly and secretion is critical for lipid absorption and triglyceride homeostasis, and plays a role in atherogenesis and the pathobiology of type 2 diabetes and obesity. This review highlights recent insights into the evolutionary, structural, and cell biology of hepatic and intestinal pathways for lipid mobilization, and the mechanisms and regulation of lipoprotein assembly and secretion.
RECENT FINDINGS
Until recently it was assumed that microsomal triglyceride transfer protein-dependent apolipoprotein B-containing lipoprotein assembly was a unique adaptation associated with vertebrate lipid homeostasis. However, it is now clear that microsomal triglyceride transfer protein (MTP) exists in species whose last common ancestor diverged over 550 million years ago. In its long evolutionary history, the MTP gene has given rise to a series of paralogous lipid transport proteins, all of which require MTP for their biogenesis. During its evolution, MTP has acquired new functions, enabling it to participate in a disparate array of lipid mobilization and transport pathways, ranging from primitive lipoprotein assembly to antigenic lipid presentation. In addition to the complex and multifunctional role of MTP in apolipoprotein B assembly, other factors responsible for the generation of secretion-coupled lipids and the modulation of apolipoprotein B production are emerging.
SUMMARY
The phylogenic dissection of MTP and apolipoprotein B function, coupled with ongoing structural and biochemical analyses, provide significant insights into the mechanisms of lipid mobilization and secretion. Some of these factors and processes may be targeted therapeutically to modulate the quantitative and qualitative aspects of apolipoprotein B production.
Topics: Apolipoproteins B; Carrier Proteins; Evolution, Molecular; Homeostasis; Humans; Lipid Metabolism; Microsomes; Triglycerides
PubMed: 15891394
DOI: 10.1097/01.mol.0000169353.12772.eb -
Journal of Lipid Research Oct 1990Apolipoprotein B (apoB), an apolipoprotein associated with very low density lipoproteins and the atherogenic low density lipoproteins (LDL), directs the metabolism of...
Apolipoprotein B (apoB), an apolipoprotein associated with very low density lipoproteins and the atherogenic low density lipoproteins (LDL), directs the metabolism of lipoprotein particles in plasma by interacting with the LDL receptor. Utilizing human intestinal biopsy organ cultures, we have studied the synthesis of intestinal apoB in man. Intestinal organ cultures from normal adults (n = 6) were incubated in the presence of protease inhibitors in media supplemented with [35S]methionine. Media from these cultures were evaluated by sequential NaDodSO4 polyacrylamide gel electrophoresis, radioautography, and Western blot analyses, and intestinal biopsies were studied using immunohistochemistry. The relative abundance of apoB-100 and apoB-48 mRNA was assessed using reverse transcriptase-polymerase chain reaction followed by primer extension. Although apoB-48 was the principal isoprotein that was newly synthesized by intestinal organ cultures, apoB-100 was also synthesized and secreted by human intestinal organ cultures with 16 +/- 3% of the intestinal apoB mRNA coding for apoB-100. These results establish that apoB-100 is produced by the human intestine. The synthesis of the atherogenic apoB-100 by the intestine has pathophysiologic implications for the development of diet-induced atherosclerosis.
Topics: Adult; Apolipoprotein B-100; Apolipoprotein B-48; Apolipoproteins B; Base Sequence; Blotting, Western; Electrophoresis, Polyacrylamide Gel; Humans; Immunohistochemistry; Intestinal Mucosa; Molecular Sequence Data; Organ Culture Techniques; Protease Inhibitors; RNA, Messenger
PubMed: 2079601
DOI: No ID Found -
Current Opinion in Lipidology Aug 2010Mipomersen is a second-generation antisense oligonucleotide developed to inhibit the synthesis of apolipoprotein B-100 in the liver. In this review we will summarize the... (Review)
Review
PURPOSE OF REVIEW
Mipomersen is a second-generation antisense oligonucleotide developed to inhibit the synthesis of apolipoprotein B-100 in the liver. In this review we will summarize the results of recent preclinical and clinical studies addressing safety and low-density lipoprotein-cholesterol (LDL-c) lowering efficacy of this new compound.
RECENT FINDINGS
In phase 3 clinical trials, mipomersen has been shown to significantly reduce LDL-c in patients with homozygous and heterozygous familial hypercholesterolemia on maximally tolerated lipid-lowering therapy. Injection site reactions, flu-like symptoms and increases in liver transaminases were the main adverse events. A recent safety study, designed to investigate the effects of mipomersen on intrahepatic triglyceride content, failed to show evidence of clinically relevant hepatic steatosis after 13 weeks of treatment.
SUMMARY
Mipomersen is a new agent to lower LDL-c in patients at increased risk of cardiovascular disease and/or intolerant to statins. Whereas safety concerns have focused on hepatic fat accumulation, to date no evidence of clinically relevant increases of intrahepatic triglyceride content are reported. Ongoing and future studies are eagerly awaited to assess the impact of mipomersen on hepatic triglyceride content after prolonged exposure.
Topics: Animals; Apolipoproteins B; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Oligonucleotides; Protein Biosynthesis
PubMed: 20508521
DOI: 10.1097/MOL.0b013e32833af4c1 -
Biological & Pharmaceutical Bulletin 2016Increased levels of apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoproteins (LDL) and chylomicron remnants, are associated with the development... (Review)
Review
Increased levels of apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoproteins (LDL) and chylomicron remnants, are associated with the development of atherosclerosis. Chylomicrons containing apoB-48 are secreted from the intestine during the postprandial state, whereas very low density lipoproteins (VLDL) containing apoB-100 are constitutively formed in the liver. Chylomicron remnants and VLDL remnants are produced by the lipoprotein lipase-mediated lipolysis of triglycerides, which is activated by apolipoprotein C-II bound on the particle surfaces. The hepatic uptake of these remnants is facilitated by apolipoprotein E (apoE), but is inhibited by apolipoproteins C-I, C-II and C-III. In the plasma, VLDL remnants are further converted into LDL by the hydrolysis of triglycerides. ApoB-100 is responsible for the hepatic uptake of LDL. LDL receptor, LDL receptor-related protein and heparan sulfate proteoglycans are involved in the hepatic clearance of lipoproteins containing apoB-100 and/or apoE. The subendothelial retention and modification of apoB-containing lipoproteins are crucial events in the initiation of atherosclerosis. In the subendothelium, the uptake of modified lipoproteins by macrophages leads to the formation of foam cells storing excess amounts of cholesteryl esters and subsequently to apoptosis. This review describes the current knowledge about the metabolism and modification of apoB-containing lipoproteins involved in dyslipidemia and atherogenesis. In particular, I focus on the effects of apolipoproteins, lipid composition and particle size on lipoprotein metabolism and on the roles of cholesterol, sphingomyelinase and apoB denaturation in macrophage foam cell formation and apoptosis. A detailed understanding of these mechanisms will help to develop new therapeutic strategies.
Topics: Apolipoproteins B; Atherosclerosis; Dyslipidemias; Humans
PubMed: 26725424
DOI: 10.1248/bpb.b15-00716 -
Methods in Enzymology 1996
Topics: Animals; Apolipoprotein B-100; Apolipoprotein B-48; Apolipoproteins B; Blood Proteins; Chromatography, Agarose; Chromatography, Gel; Coloring Agents; Electrophoresis, Polyacrylamide Gel; Gold Colloid; Humans; Lipoproteins; Precipitin Tests; Rats; Sodium Dodecyl Sulfate
PubMed: 8749003
DOI: 10.1016/s0076-6879(96)63008-0 -
Journal of Lipid Research Apr 1995We have developed a procedure to quantify apolipoprotein (apo) B-100, apoB-48, and apoE in human triglyceride-rich lipoproteins. This procedure permits delipidation of...
We have developed a procedure to quantify apolipoprotein (apo) B-100, apoB-48, and apoE in human triglyceride-rich lipoproteins. This procedure permits delipidation of small amounts of triglyceride-rich lipoproteins without appreciable losses, and quantification of these apolipoproteins in samples containing as little as 10 micrograms of protein. Delipidated triglyceride-rich lipoproteins are subjected to sodium dodecyl sulfate polyacrylamide slab gel electrophoresis, and the mass of apolipoproteins is estimated after densitometric scanning and volume integration of Coomassie blue-stained bands. The chromogenicities of apoB-100 and apoB-48 are virtually identical, and twofold lower than that of apoE. The standard curve for each apolipoprotein follows a power function over a wide protein range, permitting quantification of as little as 0.2 microgram of apoB-48 and as much as 30 micrograms of apoB-100 from a single application of triglyceride-rich lipoproteins to the gels. This method is suitable for routine use in studies of the intestinal and hepatic contributions to triglyceride-rich lipoproteins and their responses to postprandial lipemia.
Topics: Apolipoprotein B-100; Apolipoprotein B-48; Apolipoproteins B; Apolipoproteins E; Electrophoresis, Polyacrylamide Gel; Humans; Lipoproteins; Triglycerides
PubMed: 7616130
DOI: No ID Found -
Archives of Disease in Childhood. Fetal... Nov 1995
Review
Topics: Apolipoproteins B; DNA Mutational Analysis; Humans; Infant, Newborn; Pulmonary Alveolar Proteinosis; Pulmonary Surfactants
PubMed: 8535866
DOI: 10.1136/fn.73.3.f125 -
Physiological Research 2001Apolipoprotein (apo) B-100 is a key protein compound of plasma lipid metabolism. This protein, as a sole component of LDL particles, to a great extent controls the... (Review)
Review
Apolipoprotein (apo) B-100 is a key protein compound of plasma lipid metabolism. This protein, as a sole component of LDL particles, to a great extent controls the homeostasis of LDL cholesterol in the plasma. Therefore, this protein and its structural variants play an important role in development of hyperlipidemia and atherosclerosis. Intensive research into the structure and biological functions of apoB-100 has led to identification of its complete structure as well as the responsible binding sites. With the development of the methods of molecular biology, some structural variants of the apoB-100 protein that directly affect its binding properties have been described. These are mutations leading to amino acid substitution at positions 3500 (R3500Q and R3500W) and 3531 (R3531C) that have been shown to decrease the binding affinity of apoB-100 in vitro. However, only the former mutations have been unequivocally demonstrated to cause hyperlipidemia in vivo. This minireview is aimed to discuss the impact of apoB-100 and its structural variants on plasma lipid metabolism and development of hyperlipidemia.
Topics: Apolipoprotein B-100; Apolipoproteins B; Arteriosclerosis; Humans; Hyperlipidemias; Mutation
PubMed: 11551138
DOI: No ID Found