Analysis of low-density lipoprotein catabolism by primary cultures of hepatic cells from normal and low-density lipoprotein receptor knockout mice

Truong, To Quyen; Auger, Anick; Denizeau, Francine; Brissette, Louise

doi:10.1016/s1388-1981(00)00023-8

Cited by 24 publications

(21 citation statements)

References 32 publications

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“…High levels of cellular cholesterol may affect macrophage viability [13,26]. Since LDL uptake can occur via LDLRindependent pathway(s), low affinity adsorptive endocytosis, fluid phase endocytosis (pinocytosis) or other receptors may affect T. gondii in macrophages treated with 100 g/ mL LDL [25]. We observed that viabilities of wild type and LDLR KO macrophages treated with 100 g/mL LDL were slightly inhibited (data not shown).…”

Section: Effects Of Cholesterol From Host Ldl On T Gondii Growth In mentioning

confidence: 78%

Host Cholesterol Synthesis Contributes to Growth of Intracellular Toxoplasma gondii in Macrophages

Nishikawa

Ibrahim

Kameyama

et al. 2011

The Journal of Veterinary Medical Science

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ABSTRACT. The intracellular protozoan Toxoplasma gondii lacks the ability to synthesize sterol and scavenges cholesterol from the lowdensity lipoprotein receptor (LDLR) pathway of its host to facilitate replication. Sterol biosynthesis inhibitors, however, have a demonstrated anti-Toxoplasma effect. In this study, we examined the host mevalonate pathway as a novel source of cholesterol for T. gondii and its effects on parasite growth in macrophages. Parasite growth did not significantly change in the absence of LDLR or when LDL was exogenously supplemented. Lovastatin and compactin, both inhibitors of hydroxymethylglutaryl-CoA (HMG-CoA) reductase in the mevalonate pathway, significantly inhibited T. gondii growth in both wild-type and LDLR-knockout macrophages. Parasite growth was also suppressed by squalestatin, an inhibitor of squalene synthase, despite mevalonate producing isoprenoid intermediates in host cells. The present study demonstrates that lovastatin, compactin and squalestatin have anti-Toxoplasma activities and that the host cholesterol synthesis may contribute to parasite growth in macrophages.

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Section: Effects Of Cholesterol From Host Ldl On T Gondii Growth In mentioning

confidence: 78%

Host Cholesterol Synthesis Contributes to Growth of Intracellular Toxoplasma gondii in Macrophages

Nishikawa

Ibrahim

Kameyama

et al. 2011

The Journal of Veterinary Medical Science

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Section: Introductionmentioning

confidence: 95%

“…This animal model shows delayed clearance of triglyceride-rich lipoproteins and elevated circulating cholesterol, these factors resulting in atherosclerosis (Truong et al, 2000). On the other hand, it has been documented that rem-nant lipoprotein particles (RLP) isolated by an immunoseparation method evoke endothelial vasomotor dysfunction in human coronary arteries, and endothelium-derived reactive oxygen species initiate and propagate chains of free radical reactions in polyunsaturated fatty acid in RLP (Kugiyama et al, 1998;Doi et al, 2000).…”

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confidence: 99%

Cilostazol Reduces Atherosclerosis by Inhibition of Superoxide and Tumor Necrosis Factor-α Formation in Low-Density Lipoprotein Receptor-Null Mice Fed High Cholesterol

Lee

Oh²,

Park

et al. 2005

J Pharmacol Exp Ther

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This study shows that 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H)-quinolinone (cilostazol) suppresses the atherosclerotic lesion formation in the low-density lipoprotein receptor (Ldlr)-null mice. Ldlr-null mice fed a high cholesterol diet showed multiple plaque lesions in the proximal ascending aorta including aortic sinus, accompanied by increased macrophage accumulation with increased expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). Supplementation of cilostazol (0.2% w/w) in diet significantly decreased the plaque lesions with reduced macrophage accumulation and suppression of VCAM-1 and MCP-1 in situ. Increased superoxide and tumor necrosis factor-␣ (TNF-␣) production were significantly lowered by cilostazol in situ as well as in cultured human umbilical vein endothelial cells (HUVECs). TNF-␣-induced increased inhibitory B␣ degradation in the cytoplasm and nuclear factor-B (NF-B) p65 activation in the nuclei of HUVECs were reversed by cilostazol (1 ϳ 100 M) as well as by (E)-3[(4-t-butylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7085) (10 M), suggesting that cilostazol strongly inhibits NF-B activation and p65 translocation into the nuclei. Furthermore, in gel shift and DNA-binding assay, cilostazol inhibited NF-B/DNA complex and nuclear DNA-binding activity of the NF-B in the nuclear extracts of the RAW 264.7 cells. Taken together, it is suggested that the antiatherogenic effect of cilostazol in cholesterol-fed Ldlr-null mice is ascribed to its property to suppress superoxide and TNF-␣ formation, and thereby reducing NF-B activation/transcription, VCAM-1/MCP-1 expressions, and monocyte recruitments.Evidence accumulates that atherogenesis is closely related to the inflammatory and proliferative responses of the endothelium after injury (Ross, 1993). During early stages of the atherosclerosis, adhesion and chemoattractant molecules, including vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1), are secreted by the activated endothelial cells in the atherosclerotic lesions, by which the immune cells and monocytes are recruited and migrated into the intimal area of the vascular wall (Reape and Groot, 1999). Reactive oxygen species and TNF-␣ are critically implicated not only in the induction of endothelial apoptosis (Dimmeler et al., 1998) but also in the development and progression of atherosclerotic lesions in humans (Meyer et al., 1999).Inactive NF-B resides in the cytoplasm bound by its inhibitory subunit, IB␣ (Pahl, 1999). Inflammatory stimuli including TNF-␣ and endotoxin lead to degradation of IB␣ by its phosphorylation pathway (Chen et al., 1995), which allows translocation of active NF-B into the nucleus, where it regulates gene expression and binds to the promoter of the target genes such as VCAM-1 and MCP-1.The low-density lipoprotein receptor (Ldlr)-null mouse is an animal model of homozygous familial hypercholesterolemia characterized by an absence of functional LDL receptors. Th...

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“…Hepatic cells were isolated from mouse liver as described previously (9,35). Briefly, the portal vein was cannulated with a 23 gauge plastic cannula.…”

Section: Preparation Of Parenchymal and Nonparenchymal Cells From Moumentioning

confidence: 99%

“…In contrast, clearance of HDL cholesterol seems to be accomplished by another pathway called selective uptake, which involves the extraction of cholesteryl esters (CEs) from lipoproteins without concomitant degradation of its apolipoproteins (5). Although selective uptake is usually associated with HDL cholesterol, evidence suggests that this pathway may also act on other lipoproteins, such as LDL (6)(7)(8)(9).…”

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confidence: 99%

Physiological importance of SR-BI in the in vivo metabolism of human HDL and LDL in male and female mice

Brodeur

Luangrath

Bourret

et al. 2005

Journal of Lipid Research

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The physiological role of murine scavenger receptor class B type I (SR-BI) was evaluated by in vivo clearances of human HDL 3 and LDL in normal and SR-BI knockout (KO) mice. In normal mice, cholesteryl esters (CEs) were removed faster than proteins, indicating a selective uptake process from both HDL 3 and LDL. SR-BI KO mice showed 80% losses of HDL-CE selective uptake and the complete loss of LDL-CE selective uptake in the first phase of clearance. However, the second phase was characterized by an acceleration of CE disappearance in SR-BI KO mice. Thus, SR-BI is the only murine receptor mediating HDL-CE selective uptake, whereas a SR-BI-independent pathway specific to LDL can rescue SR-BI deficiency. The analysis of LDL recovered 3 h after injection in mice from different genotypes revealed that LDLs are significantly depleted in CE (reduction from 19% to 50% of the CE/protein ratios). A smaller LDL size in comparison with that of noninjected LDL was also detectable but was more evident for LDL recovered from normal mice. All LDL preparations migrate faster than noninjected LDL on agarose-barbital gels. Thus, both SR-BI-dependent and -independent pathways lead to substantial changes in LDL. Numerous epidemiological studies have demonstrated that the risk of developing coronary artery diseases is directly related to plasma concentrations of LDL cholesterol (1) and inversely associated with plasma levels of HDL (2). Plasma levels of LDL cholesterol are in large part regulated via the LDL receptor (LDLr), which mediates the clearance of LDL through a well-defined process involving endocytosis and degradation of the entire LDL particle (3, 4). In contrast, clearance of HDL cholesterol seems to be accomplished by another pathway called selective uptake, which involves the extraction of cholesteryl esters (CEs) from lipoproteins without concomitant degradation of its apolipoproteins (5). Although selective uptake is usually associated with HDL cholesterol, evidence suggests that this pathway may also act on other lipoproteins, such as LDL (6-9).The scavenger receptor class B type I (SR-BI) is a cell surface receptor that was initially found as a receptor for modified LDL (oxidized or acetylated) and maleylated BSA and was later shown to bind native lipoproteins (5, 10, 11). Although SR-BI can bind LDL with high affinity, attention has mainly been devoted to the relation between SR-BI and HDL, and SR-BI was demonstrated to mediate the selective uptake of HDL-CE in transfected cells (5,12,13). The abundance of SR-BI in steroidogenic organs and liver, the principal sites of cholesteryl ester selective uptake in vivo, has also been cited as an indication of SR-BI involvement in HDL metabolism (5, 14). However, the most convincing evidence for a role of SR-BI in HDL metabolism has come from studies using genetically manipulated mice. These studies demonstrated that a disruption of the SR-BI gene generates an increase in total plasma cholesterol levels, which is mainly associated with the appearance of large HDLs ...

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Analysis of low-density lipoprotein catabolism by primary cultures of hepatic cells from normal and low-density lipoprotein receptor knockout mice

Cited by 24 publications

References 32 publications

Host Cholesterol Synthesis Contributes to Growth of Intracellular Toxoplasma gondii in Macrophages

Host Cholesterol Synthesis Contributes to Growth of Intracellular Toxoplasma gondii in Macrophages

Cilostazol Reduces Atherosclerosis by Inhibition of Superoxide and Tumor Necrosis Factor-α Formation in Low-Density Lipoprotein Receptor-Null Mice Fed High Cholesterol

Physiological importance of SR-BI in the in vivo metabolism of human HDL and LDL in male and female mice

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