Intracellular Assembly of VLDL

Olofsson, Sven-Olof; Stillemark-Billton, Pia; Asp, Lennart

doi:10.1016/s1050-1738(01)00071-8

Cited by 132 publications

(95 citation statements)

References 68 publications

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“…In the intestine, apoB plays a vital role in the assembly of chylomicrons and in the uptake of dietary fats. The human apoB gene yields two proteins, apoB-100 and apoB-48 (6,(8)(9)(10). ApoB-48 contains the N-terminal portion 2,152 amino acids of apoB-100 and is formed as a result of apoB mRNA editing, which changes apoB codon 2153 to a stop codon.…”

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confidence: 99%

An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis

Crooke

Graham

Lemonidis

et al. 2005

Journal of Lipid Research

209

152

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High levels of plasma apolipoprotein B-100 (apoB-100), the principal apolipoprotein of LDL, are associated with cardiovascular disease. We hypothesized that suppression of apoB-100 mRNA by an antisense oligonucleotide (ASO) would reduce LDL cholesterol (LDL-C). Because most of the plasma apoB is made in the liver, and antisense drugs distribute to that organ, we tested the effects of a mouse-specific apoB-100 ASO in several mouse models of hyperlipidemia, including C57BL/6 mice fed a high-fat diet, Apoe -deficient mice, and Ldlr -deficient mice. The lead apoB-100 antisense compound, ISIS 147764, reduced apoB-100 mRNA levels in the liver and serum apoB-100 levels in a dose-and time-dependent manner. Consistent with those findings, total cholesterol and LDL-C decreased by 25-55% and 40-88%, respectively.Unlike small-molecule inhibitors of microsomal triglyceride transfer protein, ISIS 147764 did not produce hepatic or intestinal steatosis and did not affect dietary fat absorption or elevate plasma transaminase levels. These findings, as well as those derived from interim phase I data with a human apoB-100 antisense drug, suggest that antisense inhibition of this target may be a safe and effective approach for the treatment of humans with hyperlipidemia.

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confidence: 99%

An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis

Crooke

Graham

Lemonidis

et al. 2005

Journal of Lipid Research

209

152

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“…The assembly of VLDL is a complex process (Figure; for review, see Olofsson et al 16,17 ) which starts in the rough endoplasmic reticulum (rough ER) during the biosynthesis of apoB-100. The protein is lipidized by MTP (the microsomal triglyceride protein) during its biosynthesis and simultaneous translocation to the lumen of the rough ER, forming a primordial particle (a pre-VLDL).…”

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confidence: 99%

“…This transfer involves an ARF1 (ADP ribosylation factor 1)/COP I (coatomere I)-dependent sorting process from the ERGIC (ER-Golgi intermediate compartment) to the cis-Golgi. 19 This sorting process explains the ARF 1 dependence of VLDL assembly 17 Is apoA-V involved somewhere in this process? The available results are mainly based on the secretion of VLDL, usually in triton experiments (triton inhibits LPL).…”

Section: See Page 1186mentioning

confidence: 99%

“…It has also been suggested that VLDL is formed by the fusion of pre-VLDL with such droplets. 17,20 There are several ways by which this lipidation process could be influenced by amphipathic/hydrophobic proteins such as apoA-V. It is possible that apoA-V can interact with both the amphipathic monolayer of a membrane and the surface of a lipid droplet to modify the structure and availability of this pool for lipoprotein assembly.…”

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confidence: 99%

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ApoA-V

Olofsson

2005

ATVB

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See page 1186ApoA-V is involved in the regulation of plasma triglyceride levels. Thus, human apoA-V transgenic mice have lower triglyceride levels than controls, whereas the knockouts have increased levels. 1 Because hypertriglyceridemia is an independent risk factor for the development of atherosclerosis and cardiovascular diseases, elucidation of the mechanism behind the regulation of apoA-V is of great importance.Expression of apoA-V is increased by interaction of the heterodimer PPAR␣ (peroxisome proliferator-activator receptor)/RXR (retinoid X receptor) with a "Direct Repeat"1 (DR1) sequence in the apoA-V promoter. 3,4 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Genoux et al 5 show that the retinoid-related orphan receptors alpha (ROR␣) 1 and 4 are also involved in the regulation of the apoA-V gene by interaction with the DR1 binding site. This interaction occurs with the human gene but not in mice, which is logical because the motive is not conserved in mice.ROR␣ has been crystallized with cholesterol in the binding site. 6 Also, cholesterol stabilizes ROR␣, and depletion of cellular cholesterol by statins has been shown to modulate the transcriptional activity of ROR␣. 6 For a review, see Boukhtouche et al. 7 However, it remains to be clarified whether cholesterol is a physiological ligand for ROR␣.The connection between apoA-V and ROR␣ opens up interesting possibilities, because ROR␣ has been shown to prevent atherosclerosis (see Boukhtouche et al 7 for review). Thus, both the knockout mice and the natural knockout, the so-called staggerer mice, have an increased frequency of atherosclerosis (see Boukhtouche et al 7 for review).ROR␣ has previously been shown to regulate the expression of apoA-I, which may be one of the reasons why the receptor prevents atherosclerosis. Moreover, it has been shown to inhibit inflammatory responses in smooth muscle cells by transcriptional regulation of the I-B␣ gene, which codes for the inhibitor of NF-B transcription factor activity. Thus, ROR␣ interferes with the signaling pathway of NF-B (see Boukhtouche et al 7 for review). It should also be kept in mind that ROR␣ appears to have an important role in lipid homeostasis in skeletal muscle. 8 Such an effect may affect the insulin sensitivity, thereby giving rise to a reduced incidence of atherosclerosis.Because hypertriglyceridemia is an independent risk factor for atherosclerosis, the observation that ROR␣ regulates apoA-V 5 may indicate that this protein must also be taken into account when explaining the antiatherogenic effect of ROR␣.What is the role of apoA-V in the regulation of plasma triglyceride levels? Two mechanisms have been proposed: (1) that apoA-V influences the removal of triglycerides from plasma; and (2) that apoA-V influences the secretion of VLDL.Degradation of plasma triglycerides is catalyzed by the enzyme lipoprotein lipase (LPL). This enzyme is mainly expressed in adipose tissue and muscle, and acts bound to the proteoglycans on the endothelial cells of the vasculature in...

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“…Immunoelectron microscopy (1) and kinetic studies (2,3) indicate that VLDLs are assembled in two major steps (4,5). The first step occurs during the translation of apolipoprotein B (apoB) and gives rise to a premature particle (2, 6) we refer to as a primordial lipoprotein.…”

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Relation of the size and intracellular sorting of apoB to the formation of VLDL 1 and VLDL 2

Stillemark-Billton

Beck

Borén

et al. 2005

Journal of Lipid Research

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In this study, we tested the hypothesis that two separate pathways, the two-step process and an apolipoprotein B (apoB) size-dependent lipidation process, give rise to different lipoproteins. Expression of apoB-100 and C-terminally truncated forms of apoB-100 in McA-RH7777 cells demonstrated that VLDL particles can be assembled by apoB size-dependent linear lipidation, resulting in particles whose density is inversely related to the size of apoB. This lipidation results in a LDL-VLDL 2 particle containing apoB-100. VLDL 1 is assembled by the two-step process by apoB-48 and larger forms of apoB but not to any significant amount by apoB-41. The major amount of intracellular apoB-80 and apoB-100 banded with a mean density of 1.10 g/ml. Its formation was dependent on the sequence between apoB-72 and apoB-90. This dense particle, which is retained in the cell, possibly by chaperones or association with the microsomal membrane, is a precursor of secreted VLDL 1. The intracellular LDL-VLDL 2 particles formed during size-dependent lipidation appear to be the precursors of intracellular VLDL 1. We propose that the dense apoB-100 intracellular particle is converted to LDL-VLDL 2 by size-dependent lipidation. LDL-VLDL 2 is secreted or converted to VLDL 1 by the uptake of the major amount of triglycerides. -Stillemark-Billton, P., C. Beck, J. Immunoelectron microscopy (1) and kinetic studies (2, 3) indicate that VLDLs are assembled in two major steps (4, 5). The first step occurs during the translation of apolipoprotein B (apoB) and gives rise to a premature particle (2, 6) we refer to as a primordial lipoprotein. Major amounts of lipid are added in the second step, resulting in bona fide VLDL (2, 7, 8); a second precursor of VLDL, an apoB-free "lipid droplet" in the smooth endoplasmic reticulum (1, 9) whose assembly requires microsomal triglyceride transfer protein (MTP), may also be involved (10). VLDLs are secreted in two forms: large, triglyceride-rich VLDL 1 and smaller, triglyceride-poor VLDL 2. Overproduction of VLDL 1 is linked to conditions such as insulin resistance and type II diabetes (11).The lengths of C-terminally truncated forms of apoB-100 are inversely related to the amount of lipid in the lipoproteins they assemble; assembly with apoB-100 results in VLDL (12). This size-dependent lipidation of apoB does not fit the two-step model; in particular, it cannot explain why apoB-48 has the ability to assemble VLDL but apoB-40 lacks this ability (8).In this study, we tested the hypothesis that two separate pathways, the two-step process and an apoB size-dependent lipidation process, give rise to different lipoproteins. Our results indicate that although apoB can assemble VLDL 1 once it reaches the size of apoB-48, the size-dependent process gives rise to LDL-VLDL 2 particles first when apoB-100 is reached. In contrast to apoB-48 (2), the major intracellular form of apoB-100 is much denser than expected from the size/density relation, and it is retained in the secretory pathway. The sequence between apoB-7...

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Intracellular Assembly of VLDL

Cited by 132 publications

References 68 publications

An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis

An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis

ApoA-V

Relation of the size and intracellular sorting of apoB to the formation of VLDL 1 and VLDL 2

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