scholarly journals HDLs extract lipophilic drugs from cells

2021 ◽  
Author(s):  
Adi Zheng ◽  
Gilles Dubuis ◽  
Maria Georgieva ◽  
Carla Susana Mendes Ferreira ◽  
Marc Serulla ◽  
...  
Keyword(s):  
Therapeutic Benefit ◽  
Low Density Lipoproteins ◽  
High Density Lipoproteins ◽  
Drug Efflux ◽  
Cell Content ◽  
Lipophilic Compounds ◽  
Lipophilic Drugs ◽  
Er Stress Response ◽  
Underlying Mechanisms ◽  
Independent Effects

High-density lipoproteins (HDLs) prevent cell death induced by a variety of cytotoxic drugs. The underlying mechanisms are however still poorly understood. Here we present evidence that HDLs efficiently protect cells against thapsigargin (TG), a sarco/ endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) inhibitor, by extracting the drug from cells. Drug efflux could also be triggered to some extent by low-density lipoproteins and serum. HDLs did not reverse the non-lethal mild ER stress response induced by low TG concentrations or by SERCA knock-down but HDLs inhibited the toxic SERCA-independent effects mediated by high TG concentrations. HDLs could extract other lipophilic compounds, but not hydrophilic substances This work shows that HDLs utilize their capacity of loading themselves with lipophilic compounds, akin to their ability to extract cellular cholesterol, to reduce the cell content of hydrophobic drugs. This can be beneficial if lipophilic xenobiotics are toxic but may be detrimental to the therapeutic benefit of lipophilic drugs such as glibenclamide.

scholarly journals HDLs extract lipophilic drugs from cells

2020 ◽  
Author(s):  
Adi Zheng ◽  
Gilles Dubuis ◽  
Carla Susana Mendes Ferreira ◽  
Thomas Mercier ◽  
Laurent Decosterd ◽  
...  
Keyword(s):  
Drug Efficacy ◽  
Therapeutic Benefit ◽  
High Density Lipoproteins ◽  
Drug Efflux ◽  
Cell Content ◽  
Lipophilic Compounds ◽  
Lipophilic Drugs ◽  
Er Stress Response ◽  
Underlying Mechanisms ◽  
Independent Effects

AbstractHigh-density lipoproteins (HDLs) prevent cell death induced by a variety of cytotoxic drugs. The underlying mechanisms are however still poorly understood. Here we present evidence that HDLs efficiently protect cells against thapsigargin (a SERCA inhibitor) by extracting the drug from cells. Drug efflux could also be triggered to some extent by low-density lipoproteins (LDLs) and serum, which contains lipoproteins. HDLs did not reverse the non-lethal mild endoplasmic reticulum (ER) stress response induced by low thapsigargin concentrations or by SERCA knock-down but HDLs inhibited the toxic SERCA-independent effects mediated by high thapsigargin concentrations. HDLs were also found to extract other lipophilic compounds, such as the anti-diabetic drug glibenclamide. In contrast, hydrophilic substances (doxorubicin hydrochloride, rhodamine 123) were not extracted from cells by HDLs. This work shows that HDLs utilize their capacity of loading themselves with lipophilic compounds, akin to their ability to extract cellular cholesterol, to reduce the cell content of hydrophobic drugs. Silencing of the P-glycoprotein/ABCB1 transporter reduced the capacity of cells to load thapsigargin on HDLs. This work suggests that HDL-mediated cell efflux of toxic lipophilic xenobiotic is beneficial but also that HDL-mediated efflux can be detrimental to the therapeutic benefit of lipophilic drugs such as glibenclamide. Lipoprotein-mediated drug efflux should therefore be considered when evaluating drug efficacy.

Selective uptake of cholesteryl esters from various classes of lipoproteins by HepG2 cells

1999 ◽  
Vol 77 (2) ◽  
pp. 157-163 ◽  
Author(s):  
Louise Brissette ◽  
Marie-Claude Charest ◽  
Louise Falstrault ◽  
Julie Lafond ◽  
David Rhainds ◽  
...  
Keyword(s):  
Total Lipid ◽  
Hepg2 Cells ◽  
Ldl Receptor ◽  
Inverse Correlation ◽  
Low Density Lipoproteins ◽  
High Density Lipoproteins ◽  
Low Density ◽  
Cholesteryl Esters ◽  
Very Low Density Lipoproteins ◽  
Selective Uptake

Selective uptake of cholesteryl esters (CE) from lipoproteins by cells has been extensively studied with high density lipoproteins (HDL). It is only recently that such a mechanism has been attributed to intermediate and low density lipoproteins (IDL and LDL). Here, we compare the association of proteins and CE from very low density lipoproteins (VLDL), IDL, LDL and HDL3 to HepG2 cells. These lipoproteins were either labelled in proteins with 125I or in CE with 3H-cholesteryl oleate. We show that, at any lipoprotein concentration, protein association to the cells is significantly smaller for IDL, LDL, and HDL3 than CE association, but not for VLDL. At a concentration of 20 µg lipoprotein/mL, these associations reveal CE-selective uptake in the order of 2-, 4-, and 11-fold for IDL, LDL, and HDL3, respectively. These studies reveal that LDL and HDL3 are good selective donors of CE to HepG2 cells, while IDL is a poor donor and VLDL is not a donor. A significant inverse correlation (r2 = 0.973) was found between the total lipid/protein ratios of the four classes of lipoproteins and the extent of CE-selective uptake by HepG2 cells. The fate of 3H-CE of the two best CE donors (LDL and HDL3) was followed in HepG2 cells after 3 h of incubation. Cells were shown to hydrolyze approximately 25% of the 3H-CE of both lipoproteins. However, when the cells were treated with 100 µM of chloroquine, a lysosomotropic agent, 85 and 40% of 3H-CE hydrolysis was lost for LDL and HDL3, respectively. The fate of LDL and HDL3-CE in HepG2 cells deficient in LDL-receptor was found to be the same, indicating that the portion of CE hydrolysis sensitive to chloroquine is not significantly linked to LDL-receptor activity. Thus, in HepG2 cells, the magnitude of CE-selective uptake is inversely correlated with the total lipid/protein ratios of the lipoproteins and CE-selective uptake from the two best CE donors (LDL and HDL3) appears to follow different pathways.Key words: lipoprotein, receptor, HepG2 cell, selective uptake, lipid, cholesterol, binding.

Molecular bases of primary monogenic dyslipidemia

2020 ◽  
pp. 4-17
Author(s):  
О.Н. Иванова ◽  
П.А. Васильев ◽  
Е.Ю. Захарова
Keyword(s):  
Lipid Profile ◽  
Molecular Basis ◽  
Clinical Characteristics ◽  
Metabolic Disorders ◽  
Low Density Lipoproteins ◽  
Accurate Diagnosis ◽  
High Density Lipoproteins ◽  
Extreme Deviation ◽  
Low Levels ◽  
Molecular Bases

Дислипидемия - одно из наиболее распространенных метаболических нарушений, доминирующий фактор риска заболеваний сердечно-сосудистой системы. Своевременная диагностика и корректировка липидного профиля могут заметно снизить заболеваемость и смертность от сердечно-сосудистых заболеваний. Обширная гетерогенная группа заболеваний приводит к устойчивым изменениям липидного профиля. Предлагаемый обзор включает в себя описание метаболизма липидов, молекулярных основ и клинических характеристик первичных моногенных дислипидемий. Мутации двадцати пяти генов являются причиной большинства моногенных дислипидемий. На основании изменений липидного профиля выделяют пять групп фенотипов с экстремальным отклонением уровней маркеров липидного профиля: с высоким и низким уровнем липопротеинов низкой плотности, с высоким и низким уровнем липопротеинов высокой плотности, с высоким уровнем триглицеридов. Для каждого фенотипа обозначены ассоциированные гены, указан ген с чаще всего выявляемыми мутациями. Подробно описаны молекулярные основы наиболее распространенной дислипидемии, характеризующейся существенным повышением уровня липопротеинов низкой плотности - семейной гиперхолестеринемии. Генетическое тестирование пациентов с дислипидемией дает возможность постановки точного диагноза, каскадного обследования и консультирования членов семьи пациента, ранней диагностики для предотвращения или более позднего проявления осложнений. Dyslipidemia is one of the most common metabolic disorders, the dominant risk factor for diseases of the cardiovascular system. Timely diagnosis and correction of the lipid profile can significantly reduce morbidity and mortality from cardiovascular diseases. An extensive heterogeneous group of diseases leads to persistent changes in the lipid profile. This review includes a description of lipid metabolism, the molecular basis, and clinical characteristics of primary monogenic dyslipidemia. Mutations in twenty-five genes are responsible for most monogenic dyslipidemias. On the basis of changes in the lipid profile, five groups of phenotypes are distinguished with extreme deviation in the levels of lipid profile markers: with high and low levels of low density lipoproteins, with high and low levels of high density lipoproteins, with high levels of triglycerides. For each phenotype, the associated genes are indicated, the gene with the most frequently detected mutations is indicated. The molecular basis of the most common dyslipidemia, familial hypercholesterolemia, is described in detail. Genetic testing of patients with dyslipidemia makes it possible to make an accurate diagnosis, the possibility of cascade examination and counseling of the patient’s family members, the possibility of early diagnosis to prevent or later manifest complications.

scholarly journals Effect of Various Feed Phosphates on Biochemical Indices of Blood and Mineral Composition of Bones in Finishing Pigs

2010 ◽  
Vol 79 (3) ◽  
pp. 355-361 ◽  
Author(s):  
Zbigniew Dobrzański ◽  
Krystyna Pogoda-Sewerniak ◽  
Szymon Dragan ◽  
Daniel Korniewicz ◽  
Krystyna Hoffmann ◽  
...  
Keyword(s):  
Lactic Dehydrogenase ◽  
Low Density Lipoproteins ◽  
High Density Lipoproteins ◽  
Low Density ◽  
Finishing Pigs ◽  
Biochemical Indicators ◽  
Blood Biochemical ◽  
Mineral Components ◽  
Blood Biochemical Indicators ◽  
Biochemical Indices

The aim of this study was to evaluate the effect of three different chemical feed phosphates on the blood biochemical indicators and the content of main minerals of bones in finishing pigs. Over a period of 85 days of fattening, monocalcium (MCP, Finnish product), dicalcium (DCP, Polish product) and calcium-sodium (CSP, Russian product) phosphates were used in fattener feeding. The feeding was based on standard mixtures of starter, grower and finisher type. Dicalcium phosphate was produced according to the new, pro-ecological technology based on phosphoric acid. The content of Ca, Na, P, solubility of P in citric acid, and the concentration of undesirable substances (As, Cd, F, Hg and Pb) were determined in feed phosphates. At the end of the fattening period, blood was collected from 36 finishing pigs (12 from each group) and the following biochemical indicators were determined in the serum: enzymatic activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), creatine kinase (CK), lactic dehydrogenase (LDH), lactic acid (LA); the concentration of total protein, albumins, glucose, urea, creatinine, content of triglycerides, cholesterol and its high density lipoproteins (HDL) and low density lipoproteins (LDL) fractions, and mineral components concentration (Ca, Cl, Cu, Fe, K, Mg, Na, P, Zn). Basic macroelement content (Ca, Mg, P) was determined in the thigh bones from 30 pigs (10 from each group). Significant differences (p < 0.05) between groups were observed only in some biochemical indicators, i.e. CK, LDH and LA. The highest content of Ca, Mg and P was found in the bones of pigs fed mixtures supplemented with DCP which indicates improved bioavailability of main macroelements from that phosphate.

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