Low density lipoprotein receptor degradation is influenced by a mediator protein(s) with a rapid turnover rate, but is unaffected by receptor up- or down-regulation

Casciola, Livia Angela Flavia; Westhuyzen, Deneys R. van der; Gevers, Wieland; Coetzee, Gerhard A.

doi:10.1016/s0022-2275(20)38427-3

Cited by 25 publications

(5 citation statements)

References 24 publications

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“…The kinetics of down-regulation of both binding activities, in both normal and FH1 cells, were virtually identical. Surface-binding activity for both LDL and IgG-C7 decreased with a half-life of approximately 11 h, consistent with previously determined half-lives of the LDL receptor in fibroblasts (Casciola et al, 1988). Thus, both the LDLand IgG-C7-binding forms of the mutant receptor were degraded at the same rates, suggesting that while their conformational differences are sufficient to result in functional differences, they must be subtle enough not to be distinguishable by the unknown system responsible for degradation of the receptor.…”

Section: Resultssupporting

confidence: 89%

Low-density lipoprotein receptor point mutation results in expression of both active and inactive surface forms of the same mutant receptor

Coetzee²,

Gevers³

et al. 1992

Biochemistry

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LDL receptors, expressed in cultured fibroblasts from patients homozygous for the FH Afrikaner-1 (FH1) mutation (Asp206 to Glu), are transported from the endoplasmic reticulum (ER) to the Golgi apparatus more slowly than in normal cells. In the present study, binding characteristics of FH1 cells for lipoprotein ligands (LDL and beta VLDL) and for receptor-specific monoclonal antibodies pointed to the existence of two surface forms of the same mutant receptor. One of these forms bound lipoproteins with normal high affinity whereas another did not. Binding studies of transfected hamster cells expressing only the mutant human gene confirmed the single-gene origin of the different forms. The existence of functionally distinct forms of the receptor protein was supported by the observation that only lipoprotein-binding receptor molecules were trapped intracellularly and degraded following ammonium chloride treatment of cells in the presence of ligand. The lipoprotein-binding receptor population was indistinguishable from normal receptors with respect to its affinity for LDL and beta VLDL, uptake and degradation of lipoprotein, and receptor recycling. Ligand blotting versus immunoblotting of receptors revealed normal-sized mutant receptors that were not recognized by lipoprotein ligand. Despite these differences, both mutant forms of the receptor were degraded at rates similar to those of normal receptors. We propose that the single amino acid substitution in this receptor interferes with the folding and/or posttranslational processing of precursor molecules in such a way that receptors adopt alternative stable structures.

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Section: Resultssupporting

confidence: 89%

Low-density lipoprotein receptor point mutation results in expression of both active and inactive surface forms of the same mutant receptor

Coetzee²,

Gevers³

et al. 1992

Biochemistry

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“…1 Studies of LDLR turnover carried out with radiolabeled amino acids or sugars reported the half-life of LDLR in cultured human skin fibroblasts as ≈9 to 12 hours. 18–21…”

mentioning

confidence: 99%

“…1 Studies of LDLR turnover carried out with radiolabeled amino acids or sugars reported the half-life of LDLR in cultured human skin fibroblasts as ≈9 to 12 hours. [18][19][20][21] Stable isotope metabolic labeling combined with tandem mass spectrometric (MS) analysis allows measurement of turnover of targeted proteins, as well as fluxes of proteins across the global proteome. [22][23][24][25] This approach has not been used to explore the turnover of low-abundance intracellular receptors or signaling molecules and their homeostatic interactions, however.…”

mentioning

confidence: 99%

Turnover Rates of the Low-Density Lipoprotein Receptor and PCSK9: Added Dimension to the Cholesterol Homeostasis Model

Dandan

Han

Mann

et al. 2021

ATVB

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Objective: We measured the turnover rates of the LDLR (low-density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type 9) in mice by metabolic labeling with heavy water and mass spectrometry. Approach and Results: In liver of mice fed high-cholesterol diets, LDLR mRNA levels and synthesis rates were markedly lower with complete suppression of cholesterol synthesis and higher cholesterol content, consistent with the Brown-Goldstein model of tissue cholesterol homeostasis. We observed markedly lower PCSK9 mRNA levels and synthesis rates in liver and lower concentrations and synthesis rates in plasma. Hepatic LDLR half-life (t½) was prolonged, consistent with an effect of reduced PCSK9, and resulted in no reduction in hepatic LDLR content despite reduced mRNA levels and LDLR synthesis rates. These changes in PCSK9 synthesis complement and expand the well-established model of tissue cholesterol homeostasis in mouse liver, in that reduced synthesis and levels of PCSK9 counterbalance lower LDLR synthesis by promoting less LDLR catabolism, thereby maintaining uptake of LDL cholesterol into liver despite high intracellular cholesterol concentrations. Conclusions: Lower hepatic synthesis and secretion of PCSK9, an SREBP2 (sterol response element binding protein) target gene, results in longer hepatic LDLR t½ in response to cholesterol feeding in mice in the face of high intracellular cholesterol content. PCSK9 modulation opposes the canonical lowering of LDLR mRNA and synthesis by cholesterol surplus and preserves LDLR levels. The physiological and therapeutic implications of these opposing control mechanisms over liver LDLR are of interest and may reflect subservience of hepatic cholesterol homeostasis to whole body cholesterol needs.

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“…Концентрация Лп(а) в плазме крови зависит от структуры молекулы, а именно от количества кринглов IV (повторов плазминоген-подобного домена)чем их меньше, тем выше содержание частицы в периферической крови [7,9]. Высокие концентрации Лп(а) тесно связаны с атерогенным риском, формированием бляшек с тонкой крышкой в сонных артериях и развитием острых сердечно-сосудистых событий независимо от расы и различных факторов риска [10][11][12].…”

Section: ассоциация лп(а) с сердечно-сосудистыми заболеваниями оценка...unclassified

“…ти почками, достигает 3,3 сут., т.е. контакт этих частиц с сосудистой стенкой почти в 7 раз дольше, чем у ЛНП [9].…”

unclassified

Lipoprotein(a) in the diagnosis of cardiovascular risk. The values of lipoprotein (a) and apolipoprotein B in the adult population of Krasnoyarsk

Emelyanchik,

Marilovtseva,

Khomchenkov

et al. 2023

Russ J Cardiol

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Aim. To study the prevalence of elevated concentrations of lipoprotein (a) (Lp(a)) and apolipoprotein B (apoB) associated with high cardiovascular risk in a random sample of the adult Krasnoyarsk population.Material and methods. Lp(a) and apoB concentrations were determined by the immunochemiluminescent method using an automated modular Cobas 8000 platform with biochemical module c702 (Roche Diagnostic, Switzerland). We examined 263 people aged 18 to 58 who agreed to expand the standard screening by Lp(a) and apoB determination.Results. We found that high and very high levels of Lp(a) are found in 12,9% of the examined, while in women the median value was significantly higher than in men (p=0,044). In addition, 11,4% of study participants had high apoB values, regardless of sex; 3,4% of the subjects had a combination of elevated levels of ap B and Lp(a).Conclusion. Screening for Lp(a) and apoB reveals dyslipidemia associated with high cardiovascular risk in 24,3% of working-age people

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Low density lipoprotein receptor degradation is influenced by a mediator protein(s) with a rapid turnover rate, but is unaffected by receptor up- or down-regulation

Cited by 25 publications

References 24 publications

Low-density lipoprotein receptor point mutation results in expression of both active and inactive surface forms of the same mutant receptor

Low-density lipoprotein receptor point mutation results in expression of both active and inactive surface forms of the same mutant receptor

Turnover Rates of the Low-Density Lipoprotein Receptor and PCSK9: Added Dimension to the Cholesterol Homeostasis Model

Lipoprotein(a) in the diagnosis of cardiovascular risk. The values of lipoprotein (a) and apolipoprotein B in the adult population of Krasnoyarsk

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