Low-density lipoprotein receptor binding determinants switch from apolipoprotein E to apolipoprotein B during conversion of hypertriglyceridemic very-low-density lipoprotein to low-density lipoproteins.

Bradley, William A.; Hwang, S. L C; Karlin, J B; Lin, Anning; Prasad, Sarada C.; Gotto, Antonio M.; Gianturco, Sandra H.

doi:10.1016/s0021-9258(17)42663-9

Cited by 158 publications

(17 citation statements)

References 33 publications

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“…Trypsinization of VLDL removes immuno-detectable apoE on VLDL S f 100-400 (16). This VLDL subfraction is rendered LDL-receptor-inactive with the loss of its apoE receptor-binding domain on a particle in which the apoB is incompetent in binding to the LDLR (14,15,32). Both peptides studied here, Ac-hE18A-NH 2 and Ac-18A-NH 2 , bound to trypsinized VLDL as determined by SDS electrophoresis (data not shown).…”

Section: Ac-he18a-nh 2 Binds To Trypsinized Vldl and Enhances Its Uptake By Hepg2 Cellsmentioning

confidence: 71%

“…ApoE is a 299 amino acid residue protein that has been shown, initially by proteolysis studies (15,16), to have two distinct domains: a receptor binding domain in the N-terminal region [residues 1 -191] and a lipid binding domain at the C terminus [residues 192 -299]. Subsequent studies with synthetic peptides and monoclonal antibodies (17 -21) support this observation.…”

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confidence: 98%

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Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo

Datta

Garber

Chung

et al. 2001

Journal of Lipid Research

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We previously showed (1) that a peptide, Ac-hE18A-NH 2 , in which the arginine-rich heparin-binding domain of apolipoprotein E (apoE) [residues 141-150] (LRKLRKRLLR), covalently linked to 18A (DWLKAFYDKVAEKLKEAF; a class A amphipathic helix with high lipid affinity), enhanced LDL uptake and clearance. Because VLDL and remnants contain more cholesterol per particle than LDL, enhanced hepatic clearance of VLDL could lead to an effective lowering of plasma cholesterol. Therefore, in the present article we compared the ability of this peptide to mediate/facilitate the uptake and degradation of LDL and VLDL in HepG2 cells. The peptide Ac-hE18A-NH 2 , but not Ac-18A-NH 2 , enhanced the uptake of LDL by HepG2 cells 5-fold and its degradation 2-fold. The association of the peptides with VLDL resulted in the displacement of native apoE; however, only Ac-hE18A-NH 2 but not Ac-18A-NH 2 caused markedly enhanced uptake (6-fold) and degradation (3-fold) of VLDL. Ac-hE18A-NH 2 also enhanced the uptake (15-fold) and degradation (2-fold)of trypsinized VLDL Sf 100-400 (containing no immunodetectable apoE), indicating that the peptide restored the cellular interaction of VLDL in the absence of its essential native ligand (apoE). Pretreatment of HepG2s with heparinase and heparitinase abrogated all peptide-mediated enhanced cellular activity, implicating a role for cell-surface heparan sulfate proteoglycans (HSPG). Intravenous administration of Ac-hE18A-NH 2 into apoE gene knockout mice reduced plasma cholesterol by 88% at 6 h and 30% at 24 h after injection. We conclude that this dual-domain peptide associates with LDL and VLDL and results in rapid hepatic uptake via a HSPG-facilitated pathway.

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Section: Ac-he18a-nh 2 Binds To Trypsinized Vldl and Enhances Its Uptake By Hepg2 Cellsmentioning

confidence: 71%

mentioning

confidence: 98%

Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo

Datta

Garber

Chung

et al. 2001

Journal of Lipid Research

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“…More than a decade ago, Gianturco et al (18) and Bradley and colleagues (19) suggested that apoE is involved in the LDL receptor-mediated uptake of large VLDL that suppresses HMG-CoA reductase activity and later demonstrated that apoE is, in fact, necessary and sufficient for the binding of large triglyceride-rich lipoproteins to the LDL receptor (48). That these findings had a physiological significance in vivo was first indicated by Yamada et al (49,50) who showed in a rabbit model that the presence of apoE on VLDL particles influenced their elimination and conversion to LDL.…”

Section: Discussionmentioning

confidence: 99%

“…This was also illustrated by the high EC 50 values of large and small VLDL isolated from fasting plasma (52(24-110) and 48(21-103) g apoB-100/ml medium). This pattern was not seen for large or for small VLDL isolated after Intralipid infusion (EC 50 values (of 19 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) and 24(15-33) g apoB-100/ml medium, respectively). The increased capacity of the post-infusion large VLDL to inhibit LDL binding to the LDL receptor, illustrated by the significant increase in k-value, was also evident when the post-and pre-infusion EC 50 values were compared (19(12-28) vs. 52(24-110) g apoB/ml medium, P Ͻ 0.01).…”

Section: Effects Of the Triglyceride Emulsion On The Capacity Of Vldl To Inhibit Ldl Binding To The Ldl Receptor On Fibroblasts In Vitromentioning

confidence: 93%

“…In contrast, large VLDL particles of hypertriglyceridemic individuals are to a large extent removed from the plasma before reaching the S f 20-60 stage and without prior conversion to LDL (17). Whereas apoEmediated binding and uptake by the LDL receptor has been consistently shown for hypertriglyceridemic large VLDL, small VLDL and IDL (18)(19)(20), a prevailing point of view has been that most native VLDL species from normolipidemic humans are incapable of undergoing LDL receptor-mediated catabolism (18,21,22). However, cellular processing through the LDL receptor has now been demonstrated for all subfractions of normolipidemic VLDL, although the capacity for both binding and catabolism decreases with increasing particle size (23).…”

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confidence: 99%

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Transient triglyceridemia in healthy normolipidemic men increases cellular processing of large very low density lipoproteins by fibroblasts in vitro

Björkegren¹,

Karpe

Vitols

et al. 1998

Journal of Lipid Research

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Exaggerated and prolonged postprandial triglyceridemia is a characteristic of patients with precocious coronary heart disease. Although large very low density lipoprotein (VLDL) particles accumulate during alimentary lipemia, the biological properties of the postprandial VLDL remain unknown. In the present study, an intravenous infusion of a chylomicron-like emulsion was given to healthy normolipidemic men to examine the effects of transient triglyceridemia in vivo on compositional and cell biological characteristics of VLDL. The postinfusion large(Svedberg flotation rate (S f ) (60-400) VLDL was found to have increased capacity to inhibit low density lipoprotein (LDL) binding to the LDL-receptor and a greater ability to suppress the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity of cultured fibroblasts compared to VLDL isolated from fasting plasma. These alterations in cellular interactions were accompanied by increases in the number of apolipoprotein (apo) E, C-I, and C-III molecules per large VLDL particle and loss of apoC-II, compositional changes similar to those observed after an oral fat load. The increase in number of apoE molecules per large VLDL particle correlated positively and significantly with the increase in the capacity of large VLDL to inhibit LDL binding to the LDL receptor ( r ϭ 0.76, P ϭ 0.01, n ϭ 10). In contrast, the composition of the small (S f 20-60) VLDL particles did not change significantly, nor was the LDL receptor-mediated processing of these particles altered consistently.These observations indicate that large VLDL particles that accumulate during alimentary lipemia undergo compositional changes that render them more prone to cellular binding and uptake.-Björkegren, J., F. Karpe, S. Vitols, P. Tornvall, and A. Hamsten. Transient triglyceridemia in healthy normolipidemic men increases cellular processing of large very low density lipoproteins by fibroblasts in vitro.

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LDL Receptor and Its Role in Inherited Disease

Soutar

2010

Encyclopedia of Life Sciences

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The low‐density lipoprotein (LDL) receptor mediates the specific uptake of LDL from the circulation and its intracellular degradation by a process known as the LDL receptor pathway. LDL receptor gene expression is regulated by intracellular sterol content, and is limited mainly to the liver in vivo . Mutations in LDLR , the gene encoding the LDL receptor, cause familial hypercholesterolaemia (FH), a dominantly inherited disease where accumulation of LDL in the circulation increases the risk of coronary heart disease. Defects in other genes, including APOB , encoding the ligand for the LDL receptor, ARH , encoding a protein required for its internalisation and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), encoding a protein that reduces LDL receptor protein levels, cause a similar disorder because the encoded proteins are involved in the LDL receptor pathway. FH can readily be treated with cholesterol‐lowering drugs to reduce cardiovascular risk effectively, and identification of the causal genetic defect allows unequivocal and early diagnosis. Key Concepts: The LDL receptor mediates specific uptake and intracellular degradation of serum LDL. Inherited defects in the LDL receptor pathway cause familial hypercholesterolaemia (FH), characterised by increased serum LDL and increased risk of coronary heart disease. Most FH patients have mutations in LDLR , but defects in other genes cause a similar disorder. A recessive form of FH is caused by null mutations in ARH, a clathrin adaptor protein required for LDL receptor internalisation. A dominant form of FH is caused by gain‐of‐function mutations in PCSK9 , which encodes a protein that promotes degradation of LDL receptor protein. Dominant loss‐of‐function mutations in PCSK9 reduce serum cholesterol and risk of coronary heart disease. One relatively common dominant mutation in APOB , encoding the ligand for the LDL receptor, causes familial defective apoB (FDB). LDLR transcription is regulated by sterol response element‐binding proteins (SREBP) in a complex mechanism involving several other proteins. FH can readily be treated with cholesterol‐lowering drug therapy to abolish the increased risk of coronary disease, but is currently under‐diagnosed. Identifying causal mutations in known patients and screening their relatives should identify more affected individuals.

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Low-density lipoprotein receptor binding determinants switch from apolipoprotein E to apolipoprotein B during conversion of hypertriglyceridemic very-low-density lipoprotein to low-density lipoproteins.

Cited by 158 publications

References 33 publications

Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo

Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo

Transient triglyceridemia in healthy normolipidemic men increases cellular processing of large very low density lipoproteins by fibroblasts in vitro

LDL Receptor and Its Role in Inherited Disease

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