Hexadecylphosphocholine disrupts cholesterol homeostasis and induces the accumulation of free cholesterol in HepG2 tumour cells

Jiménez-López, José M.; Carrasco, Marı́a P.; Marco, Carmen; Segovia, J.L.

doi:10.1016/j.bcp.2005.08.001

Cited by 15 publications

(23 citation statements)

References 26 publications

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“…It is interesting to note that this increase in cholesterol synthesis occurred both in the presence and absence of LDL. These data agree with results published previously [8], in which we demonstrated that the exposure to HePC of HepG2 cells incubated in a medium supplemented with fetal bovine serum significantly increased the synthesis of cholesterol. Thus, the results of this work show that the cholesterogenic enhancement induced by HePC does not depend upon the presence of exogenous cholesterol in the medium.…”

Section: Discussionsupporting

confidence: 83%

“…The inhibition of CE synthesis observed after 6 h of treatment cannot be linked with any direct effect of HePC upon the ACAT enzyme because the synthesis of CE remained unaffected in membranes exposed to HePC in vitro [8].…”

Section: Controlmentioning

confidence: 99%

“…Other authors have also demonstrated that this movement of cholesterol from the plasma membrane to the ER can be inhibited under different experimental conditions, such as in the presence of hydrophobic amines [29] or progesterone [21], and by the disruption of the cytoskeleton or of the acidic compartments [10,30]. We also analysed the movement of newly synthesized cholesterol to the plasma membrane by using [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]acetate as a cholesterogenic precursor and (2-hydroxypropyl)-b-cyclodextrin as a cholesterol acceptor, as described by Yamauchi et al [31]. Our data showed that HePC treatment does not modify cholesterol transport from the ER to the plasma membrane (i.e.…”

Section: Controlmentioning

confidence: 99%

“…We reported, in a previous study, that HePC interferes with phosphatidylcholine (PtdCho) synthesis in HepG2 cells via both cytidine 5¢-diphosphocholine [6] and phosphatidylethanolamine methylation [7]. We have also demonstrated that HePC alters intracellular cholesterol metabolism, which consequently leads to a rise in the cholesterol levels of cells [8].…”

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confidence: 99%

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Hexadecylphosphocholine interferes with the intracellular transport of cholesterol in HepG2 cells

et al. 2008

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We have shown, in a previous publication, that nontoxic concentrations of hexadecylphosphocholine exert an antiproliferative effect on HepG2 cells. Hexadecylphosphocholine also interferes with the biosynthesis of cholesterol and phosphatidylcholine. We have now extended our studies to try to establish the molecular mechanism by which hexadecylphosphocholine disrupts cholesterol homeostasis. Using radiolabelled substrates we determined the effect of hexadecylphosphocholine on cholesterol synthesis, the destiny of cholesterol from low‐density lipoprotein and the transport of cholesterol between the plasma membrane and the endoplasmic reticulum. Protein levels and gene expression of the main proteins involved in cholesterol homeostasis were analysed by western blotting and RT‐PCR, respectively. HepG2 cells exposed to hexadecylphosphocholine showed an increase in cholesterol biosynthesis when acetate, but not mevalonate, was used as a substrate. The activity of 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (EC 1.1.1.34) and low‐density lipoprotein receptor, as well as the corresponding mRNA expression, increased after 24 h of treatment with hexadecylphosphocholine. Cholesteryl linoleate in low‐density lipoprotein uptake and further hydrolysis of these esters increased but the cholesterol esterification was reduced after 6 h of treatment with alkylphosphocholine. Cholesterol transport from the plasma membrane to the endoplasmic reticulum was impaired by hexadecylphosphocholine. In conclusion, hexadecylphosphocholine interfered with the transport of cholesterol from the cell surface to the endoplasmic reticulum, leading to a depletion of cholesterol in the endoplasmic reticulum and a deregulation of cholesterol biosynthesis. The accumulation of cholesterol within the cell and the reduction in phosphatidylcholine synthesis produces an alteration in the phosphatidylcholine/cholesterol ratio that may well be responsible for the antiproliferative activity exhibited by hexadecylphosphocholine in HepG2 cells.

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Section: Discussionsupporting

confidence: 83%

Section: Controlmentioning

confidence: 99%

Section: Controlmentioning

confidence: 99%

mentioning

confidence: 99%

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Hexadecylphosphocholine interferes with the intracellular transport of cholesterol in HepG2 cells

et al. 2008

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“…In leukemic cells treatment with alkylphospholipids induces the formation of membrane raft aggregates containing Fas/CD95 death receptor and the adaptor molecule Fas-associated death domain-containing protein (FADD), which are critical in the triggering of apoptosis (Gajate et al, 2009). Miltefosine and other alkylphospholipids also alter intracellular cholesterol traffic and metabolism leading to an increased uptake, synthesis and accumulation of cholesterol in the cell (Carrasco et al, 2008;Jimenez-Lopez et al, 2006;Marco et al, 2009). As cholesterol and sphingomyelin content are critical for the integrity and functionality of membrane lipid rafts, the disturbance of the cholesterol/sphingomyelin ratio could alter signaling pathways associated with these membrane domains.…”

Section: Uptake and Absorption Of Alkylphospholipidsmentioning

confidence: 99%

Interaction of Alkylphospholipid Formulations with Breast Cancer Cells in the Context of Anticancer Drug Development

Koklic¹,

Podlipec²,

Mravljak³

et al. 2011

Breast Cancer - Focusing Tumor Microenvironment, Stem Cells and Metastasis

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Lipid Efflux Mediated by Alkylphospholipids in HepG2 Cells

Ríos-Marco

Segovia

Jiménez-López

et al. 2013

Cell Biochem Biophys

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Antitumoural alkylphospholipid (APL) analogues alter cholesterol homoeostasis in HepG2 cells by interfering with cholesterol transport from the plasma membrane to the endoplasmic reticulum (ER) and at the same time stimulating the release of considerable quantities of membrane cholesterol. The capacity of APLs to stimulate cholesterol efflux is suppressed when cells are incubated simultaneously with APLs and serum whilst the inhibition of cholesterol transport to the ER (measured in terms of the synthesis of esterified cholesterol) persists, indicating that both effects are independent of each other. Interestingly, our results suggest that both raft and non-raft membrane domains contribute to the cholesterol released to APLs. In addition, a marked efflux of choline-bearing phospholipids (phosphatidylcholine (PC) and sphingomyelins (SM)) was found to be related to this release of cholesterol. Finally, we observed that APL micelles composed of cholesterol might act as donor/acceptor cholesterol systems. Thus, the findings of this study clearly demonstrate that antitumoural APLs act as extracellular acceptors, stimulating cholesterol and phospholipid efflux, although they may also play a role as cholesterol donors.

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Hexadecylphosphocholine disrupts cholesterol homeostasis and induces the accumulation of free cholesterol in HepG2 tumour cells

Cited by 15 publications

References 26 publications

Hexadecylphosphocholine interferes with the intracellular transport of cholesterol in HepG2 cells

Hexadecylphosphocholine interferes with the intracellular transport of cholesterol in HepG2 cells

Interaction of Alkylphospholipid Formulations with Breast Cancer Cells in the Context of Anticancer Drug Development

Lipid Efflux Mediated by Alkylphospholipids in HepG2 Cells

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