Triolein-cholesteryl oleate-cholesterol-lecithin emulsions: structural models of triglyceride-rich lipoproteins

Miller, Kurt W.; Small, Donald

doi:10.1021/bi00271a030

Cited by 100 publications

(53 citation statements)

References 36 publications

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“…However, since CE and TG transfers occur through a common site on CETP (21) and TG transfer is not altered, the decrease in CE transfer by FC enrichment is unlikely to result from an altered CETP conformation when bound to the modified lipoprotein surface. The data presented here support our previous hypothesis that FC reduces CE transfer from LDL by displacing CE from the surface of the lipoprotein (44), as suggested by the lipid solubility studies of Miller and Small (52,53). This mechanism is consistent with the uncompetitive inhibition kinetics noted for FC.…”

Section: Discussionsupporting

confidence: 91%

“…In a previous study, an increased FC content of LDL resulted in decreased CE transfer rates (44). It was proposed that this decrease was due to a reduction in the CE available at the lipoprotein surface since FC and CE may compete for residency in the PL monolayer (52,53). To test this hypothesis directly, the kinetics of lipid transfer from liposomes with progressively increasing CE content to FC-modified LDL ( Table 2 ) were measured.…”

Section: Ce Surface-accessibility In Ldlmentioning

confidence: 99%

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The surface cholesteryl ester content of donor and acceptor particles regulates CETP: a liposome-based approach to assess the substrate properties of lipoproteins

Morton

Greene

2003

Journal of Lipid Research

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Cholesteryl ester transfer protein (CETP) activity is regulated, in part, by lipoprotein composition. We previously demonstrated that CETP activity follows saturation kinetics as cholesteryl ester (CE) levels in the phospholipid surface of donor particles are increased. We propose here that the plateau of CETP activity occurs because the surface concentration of CE in the acceptor becomes rate limiting. This hypothesis was tested in CETP assays between synthetic liposomes whose CE content was varied independently. As donor CE increased, CETP activity followed saturable kinetics, but the slope of the first-order portion of the curve and the maximum achievable CE transfer rate were linearly related to the acceptor's surface CE concentration. Two mechanisms have been proposed for the CETPmediated transfer of lipids. The carrier model suggests that CETP binds to the lipoprotein surface, where it picks up CE or TG and diffuses through the aqueous media to dock on an acceptor lipoprotein, where it releases its bound lipids (15). Alternatively, the ternary complex model (16) suggests that CETP transfer occurs within a temporary complex between itself and two lipoproteins. It has been argued that both mechanisms may occur physiologically depending on the levels of other factors, such as free fatty acids (17). However, several detailed kinetic studies (18)(19)(20), the demonstration that CETP has a specific binding site for CE and/or TG (21), that purified CETP contains neutral lipid bound to this site (21,22), and that lipids bound to this site can be subsequently transferred to a lipoprotein (20,22) strongly implicate the carrier model as the dominant mechanism of transfer. Regardless of the functional mechanism, it is apparent that the initial obligatory step for transfer is the binding of CETP to a lipoprotein (21, 23-26) through interaction with its surface phospholipids (PLs) (18,23,24,26).Most data suggest that the transfer of CE and TG between lipoproteins is a coupled process; i.e., CETP mediates the exchange of lipids between lipoproteins rather than unidirectional flux. This is supported by some longterm mass studies where CE loss and TG gain among lipoprotein fractions are nearly equimolar (1,(27)(28)(29), and by detailed radioisotope transfer studies (30), although this coupling has not always been observed (31-33). MoreAbbreviations: CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; FC, free cholesterol; PC, phosphatidylcholine; PL, phospholipid; TG, triglyceride.

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Section: Discussionsupporting

confidence: 91%

Section: Ce Surface-accessibility In Ldlmentioning

confidence: 99%

The surface cholesteryl ester content of donor and acceptor particles regulates CETP: a liposome-based approach to assess the substrate properties of lipoproteins

Morton

Greene

2003

Journal of Lipid Research

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“…CE in storage droplets continuously undergoes hydrolysis to cholesterol and, if the cholesterol is not needed, it is transported back to the ER for reesterification and then redeposited in the droplet (48,49). In the adipocyte, we propose that the product of CE hydrolysis, cholesterol, does not readily leave the droplet because of its solubility in TG (50,51), leading to a steady state where the bulk of cholesterol in the adipocyte droplet is in the free form. This is supported by the finding that the loss of cholesterol from adipocyte droplets is minimal during the first 24 h of stimulated TG lipolysis (52, 53) but increases thereafter, suggesting that cholesterol is not released from storage droplets until the solubility limit in the TG phase is approached.…”

Section: Discussionmentioning

confidence: 99%

Possible Role for Intracellular Cholesteryl Ester Transfer Protein in Adipocyte Lipid Metabolism and Storage

Izem

Morton²

2007

Journal of Biological Chemistry

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Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester (CE) and triglyceride (TG) between lipoproteins in plasma. However, short term suppression of CETP biosynthesis in cells alters cellular cholesterol homeostasis, demonstrating an intracellular role for CETP as well. The consequences of chronic CETP deficiency in lipid-storing cells normally expressing CETP have not been reported. Here, SW872 adipocytes stably expressing antisense CETP cDNA and synthesizing 20% of normal CETP were created. CETP-deficient cells had 4-fold more CE but an ϳ3-fold decrease in cholesterol biosynthesis. This phenotype of cholesterol overload is consistent with the observed 45% reduction in low density lipoprotein receptor and 2.5-fold increase in ABCA1 levels. However, cholesterol mass in CETP-deficient adipocytes was actually reduced. Strikingly, CETP-deficient adipocytes stored <50% of normal TG, principally reflecting reduced synthesis. The hydrolysis of cellular CE and TG in CETP-deficient cells was reduced by >50%, although hydrolase/lipase activity was increased 3-fold. Notably, the incorporation of recently synthesized CE and TG into lipid storage droplets in CETP-deficient cells was just 40% of control, suggesting that these lipids are inefficiently transported to droplets where the hydrolase/lipase resides. The capacity of cellular CETP to transport CE and TG into storage droplets was directly demonstrated in vitro. Overall, chronic CETP deficiency disrupts lipid homeostasis and compromises the TG storage function of adipocytes. Inefficient CETP-mediated translocation of CE and TG from the endoplasmic reticulum to their site of storage may partially explain these defects. These studies in adipocytic cells strongly support a novel role for CETP in intracellular lipid transport and storage. Cholesteryl ester transfer protein (CETP)2 (1) mediates the transfer of cholesteryl ester (CE) and triglyceride (TG) among plasma lipoproteins (2-4). CETP is a member of the lipid transfer/lipopolysaccharide-binding protein gene family that is composed of highly hydrophobic proteins involved in lipid binding and transport (5, 6). Two CETP transcripts exist, a 1.6-kb transcript produced from the full-length, 16-exon CETP gene and a 1.4-kb transcript lacking exon 9 (180 nucleotides) derived by alternative splicing (7). mRNAs for both variants are present in all human tissues expressing CETP. When compared with the full-length form, which accounts for essentially all plasma CETP, exon 9-deleted CETP is poorly secreted, and its function is unknown (7,8). Exon 9-deleted CETP retains the amino acids that constitute the binding sites for TG and CE (residues 470 -475) (9, 10) and the bulk of the putative lipoprotein-binding region (11,12). Absence of a portion of this binding region in exon 9-deleted CETP may explain its poor interaction with HDL (8) and may lead to a variant with different substrate preference or affinity.In addition to its abundant hepatic expression, CETP is synthesized by many tissues, such as adipose, adrenal ...

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“…The weight fraction of TO in the emulsion surface monolayer of PC is independent of the relative concentration of TO in the particle or of the size of the particle. 262) Kinetic parameters of the LPL-mediated lipolysis activated by apoC-II indicate that LPL has similar apparent maximal activities in large and small emulsions. Binding parameters, dissociation constant and binding maximum, of apoC-II for large and small emulsions are similar.…”

Section: )mentioning

confidence: 95%

Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis

Morita

2016

Biological & Pharmaceutical Bulletin

133

108

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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.

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Triolein-cholesteryl oleate-cholesterol-lecithin emulsions: structural models of triglyceride-rich lipoproteins

Cited by 100 publications

References 36 publications

The surface cholesteryl ester content of donor and acceptor particles regulates CETP: a liposome-based approach to assess the substrate properties of lipoproteins

The surface cholesteryl ester content of donor and acceptor particles regulates CETP: a liposome-based approach to assess the substrate properties of lipoproteins

Possible Role for Intracellular Cholesteryl Ester Transfer Protein in Adipocyte Lipid Metabolism and Storage

Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis

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