The role of the LDL receptor in apolipoprotein B secretion

Twisk, Jaap; Gillian-Daniel, Donald L.; Tebon, Angie; Wang, Lin; Barrett, P. Hugh R.; Attie, Alan D.

doi:10.1172/jci8623

Cited by 224 publications

(210 citation statements)

References 91 publications

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“…We recently demonstrated that the presence of the LDLR greatly increases the proportion of apoB subject to presecretory degradation. Our results directly link VLDL overproduction in FH with the loss of the LDLR (6).…”

Section: Mutations In the Low Density Lipoprotein (Ldl) Receptor (Ldlr)supporting

confidence: 55%

Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B

Gillian-Daniel

Bates

Tebon

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the low density lipoprotein (LDL) receptor (LDLR)cause hypercholesterolemia because of inefficient LDL clearance from the circulation. In addition, there is a paradoxical oversecretion of the metabolic precursor of LDL, very low density lipoprotein (VLDL). We recently demonstrated that the LDLR mediates presecretory degradation of the major VLDL protein, apolipoprotein B (apoB). Kinetic studies suggested that the degradation process is initiated in the secretory pathway. Here, we evaluated the ability of several LDLR variants that are stalled within the secretory pathway to regulate apoB secretion. Both a naturally occurring mutant LDLR and an LDLR consisting of only the ligand-binding domains and a C-terminal endoplasmic reticulum (ER) retention sequence were localized to the ER and not at the cell surface. In the presence of either of the ER-localized LDLRs, apoB secretion was essentially abolished. When the ligand-binding domain of the truncated receptor was mutated the receptor was unable to block apoB secretion, indicating that the inhibition of apoB secretion depends on the ability of the LDLR to bind to its ligand. These findings establish LDLR-mediated pre-secretory apoB degradation as a pathway distinct from reuptake of nascent lipoproteins at the cell surface. The LDLR provides an example of a receptor that modulates export of its ligand from the ER.M olecular defects in the low density lipoprotein (LDL) receptor (LDLR) cause Familial Hypercholesterolemia (FH), a condition associated with elevated plasma LDL cholesterol levels (1). Reduced expression, altered ligand binding, or defective transport to the cell surface all lead to a reduction in the functionally effective population of LDLRs at the cell surface.LDL is produced in the circulation from its precursor, very low density lipoprotein (VLDL). Apolipoprotein B (apoB) is the major protein component of VLDL and LDL. Two observations have suggested that the LDLR might be involved in apoB secretion. First, overproduction of apoB-containing lipoproteins occurs in some cases of FH (2-4). Second, drugs that lower LDL levels by increasing the expression of the LDLR (statins) in many instances have been shown to lower LDL without increasing LDL clearance; i.e., they lower LDL and͞or VLDL production (5).The proportion of apoB that escapes degradation within the secretory pathway primarily determines the rate of VLDL secretion. We recently demonstrated that the presence of the LDLR greatly increases the proportion of apoB subject to presecretory degradation. Our results directly link VLDL overproduction in FH with the loss of the LDLR (6).Several additional studies support a role for the LDLR in modulating apoB secretion. Increased secretion of VLDL is observed in vivo from both Ldlr Ϫ/Ϫ and transgenic Ldlr Ϫ/Ϫ mice that overexpress the nuclear form of sterol regulatory element binding protein-1a (SREBP-1a) and in vitro in hepatocytes from these animals (7). In contrast, transgenic SREBP-1a animals with a wild-type LDLR accumulate cholesterol a...

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Section: Mutations In the Low Density Lipoprotein (Ldl) Receptor (Ldlr)supporting

confidence: 55%

Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B

Gillian-Daniel

Bates

Tebon

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…In the absence of PCSK9, it seems that there is reduced apoB48 secretion from mouse primary hepatocytes. The increase in LDLR protein expression resulting from the deletion of Pcsk9 could explain this observation by means of the mechanism described by Twisk et al (24), who previously demonstrated that the LDLR protein can mediate posttranslational presecretory degradation of apoB in hepatocytes. A second possibility is that increased LDLR expression on the cell surface mediates immediate VLDL recapture, thus reducing total apoB secretion into the medium.…”

Section: Discussionmentioning

confidence: 88%

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9

Rashid

Curtis

Garuti

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

648

529

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PCSK9 encodes proprotein convertase subtilisin͞kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR) in mice. Here, we show that livers of knockout mice lacking PCSK9 manifest increased LDLR protein but not mRNA. Increased LDLR protein led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg͞dl in Pcsk9 ؊/؊ mice versus 96 mg͞dl in WT mice). Statins, a class of drugs that inhibit cholesterol synthesis, increase expression of sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor that activates both the Ldlr and Pcsk9 genes. Statin administration to Pcsk9 ؊/؊ mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. These data demonstrate that PCSK9 regulates the amount of LDLR protein in liver and suggest that inhibitors of PCSK9 may act synergistically with statins to enhance LDLRs and reduce plasma cholesterol.low-density lipoprotein receptor ͉ lipoproteins ͉ proteinase ͉ sterol regulatory element-binding protein

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“…To better assess how well our calculations agreed with these experimental results, we performed a literature search for similar pulse-chase experiments involving 35 Cys and 35 Met labelling in which error bars are reported for proteins translating in vivo. The error bars were extracted from the published graphs of three separate studies [49][50][51] n (ref. 52).…”

Section: Methodsmentioning

confidence: 99%

Accurate Prediction of Cellular Co-Translational Folding Indicates Proteins can Switch from Post- to Co-Translational Folding

Nissley

2017

Biophysical Journal

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The rates at which domains fold and codons are translated are important factors in determining whether a nascent protein will co-translationally fold and function or misfold and malfunction. Here we develop a chemical kinetic model that calculates a protein domain's co-translational folding curve during synthesis using only the domain's bulk folding and unfolding rates and codon translation rates. We show that this model accurately predicts the course of co-translational folding measured in vivo for four different protein molecules. We then make predictions for a number of different proteins in yeast and find that synonymous codon substitutions, which change translation-elongation rates, can switch some protein domains from folding post-translationally to folding co-translationally-a result consistent with previous experimental studies. Our approach explains essential features of co-translational folding curves and predicts how varying the translation rate at different codon positions along a transcript's coding sequence affects this self-assembly process.

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The role of the LDL receptor in apolipoprotein B secretion

Cited by 224 publications

References 91 publications

Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B

Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9

Accurate Prediction of Cellular Co-Translational Folding Indicates Proteins can Switch from Post- to Co-Translational Folding

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