Apolipoprotein E Expression in Y1 Adrenal Cells Is Associated with Increased Intracellular Cholesterol Content and Reduced Free Cholesterol Efflux

Biochemistry ◽  
1994 ◽  
Vol 33 (17) ◽  
pp. 5049-5055 ◽  
Author(s):  
Margaret M. Prack ◽  
George H. Rothblat ◽  
Sandra K. Erickson ◽  
Mary E. Reyland ◽  
David L. Williams
Keyword(s):  
Apolipoprotein E ◽  
Cholesterol Efflux ◽  
Free Cholesterol ◽  
Cholesterol Content ◽  
Adrenal Cells ◽  
Intracellular Cholesterol

scholarly journals Hypocholesterolaemic effect of β β'-methyl-substituted hexadecanedioic acid (MEDICA 16) in the male hamster

1993 ◽  
Vol 289 (3) ◽  
pp. 911-917 ◽  
Author(s):  
N Mayorek ◽  
J Bar-Tana
Keyword(s):  
Cholesteryl Ester ◽  
Cholesterol Efflux ◽  
Free Cholesterol ◽  
Plasma Cholesterol ◽  
Cholesterol Acyltransferase ◽  
Cholesterol Content ◽  
Plasma Lipoproteins ◽  
Purina Chow ◽  
Apolipoprotein C ◽  
Bile Cholesterol

Treatment of cholesterol-fed male hamsters kept on a diet of purina chow with beta beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) resulted in a progressive hypocholesterolaemic effect, amounting to a 50% decrease in the cholesterol content of all plasma lipoproteins. The decrease in plasma cholesterol could be accounted for by activation of plasma-cholesterol efflux through the liver into the bile mediated by MEDICA 16-induced (a) increase of the number of liver LDL receptors, (b) activation of liver neutral cholesteryl ester hydrolase with a concomitant inhibition of liver acyl-CoA cholesterol acyltransferase, resulting in shifting of the liver cholesteryl ester/free-cholesterol cycle in the direction of free cholesterol, and (c) activation of cholesterol efflux from the liver into the bile. The increase in bile cholesterol output was accompanied by an increase in bile phospholipids but not in bile acids. In contrast with rats, MEDICA 16-treatment of male hamsters did not result in a hypotriacylglycerolaemic effect, inhibition of lipogenesis, nor in a substantial decrease in plasma apolipoprotein C-III content.

Triacylglycerol-rich lipoproteins alter the secretion, and the cholesterol-effluxing function, of apolipoprotein E-containing lipoprotein particles from human (THP-1) macrophages

2001 ◽  
Vol 356 (2) ◽  
pp. 515-523 ◽  
Author(s):  
E. Marie LINDHOLM ◽  
Anna M. PALMER ◽  
Annette GRAHAM
Keyword(s):  
Apolipoprotein E ◽  
Type Ii Diabetes ◽  
Cholesterol Efflux ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Content ◽  
Type Ii ◽  
Increased Risk ◽  
Triacylglycerol Accumulation ◽  
Dose Dependent

Elevated plasma levels of triacylglycerol-rich lipoproteins (TGRLP) are associated with increased risk of atherogenesis and abnormal reverse cholesterol transport, as illustrated in Type II diabetes. Here we examine the effect of plasma triacylglycerol-rich or cholesteryl ester-rich lipoproteins on the secretion of nascent apolipoprotein E (apoE)-containing lipoprotein E (LpE) particles by human (THP-1) macrophages. As expected, preincubation with low-density lipoprotein (LDL) yielded small but significant increases in total cellular cholesterol content and also the secretion of apoE by macrophages. By contrast, preincubation with TGRLP resulted in higher, dose-dependent, increases in apoE secretion that reflected, but were not dependent on, cellular triacylglycerol accumulation. Secreted apoE was incorporated into a pre-β migrating LpE fraction that differed in lipid composition and flotation density depending on preincubation conditions. Specifically, the LpE-containing lipoprotein fraction produced by macrophages preincubated with TGRLP was cholesterol-poor, markedly heterogeneous and of higher peak flotation density (d 1.14–1.18) when compared with particles produced after preincubation with LDL. Both the conditioned medium and the isolated (d < 1.21) LpE-containing fraction, yielded by macrophages preincubated with TGRLP, seemed poorer at inducing cholesterol efflux than the equivalent fractions from cells preincubated with LDL, as judged by [3H]cholesterol efflux from untreated ‘naïve’ macrophages. Thus, although the interaction of TGRLP with macrophages can enhance apoE output from these cells, the LpE particles produced seem to be relatively inefficient mediators of cholesterol efflux. These factors might contribute to the increased risk of atherosclerosis in individuals with Type II diabetes.

Caveolin-1 and regulation of cellular cholesterol homeostasis

2006 ◽  
Vol 291 (2) ◽  
pp. H677-H686 ◽  
Author(s):  
Philippe G. Frank ◽  
Michelle W.-C. Cheung ◽  
Stephanos Pavlides ◽  
Gemma Llaverias ◽  
David S. Park ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Free Cholesterol ◽  
Scavenger Receptor ◽  
Cholesterol Homeostasis ◽  
Type I ◽  
Wild Type ◽  
Cellular Cholesterol ◽  
Caveolin 1 ◽  
Intracellular Cholesterol ◽  
Cellular Cholesterol Efflux

Caveolae are 50- to 100-nm cell surface plasma membrane invaginations present in terminally differentiated cells. They are characterized by the presence of caveolin-1, sphingolipids, and cholesterol. Caveolin-1 is thought to play an important role in the regulation of cellular cholesterol homeostasis, a process that needs to be properly controlled to limit and prevent cholesterol accumulation and eventually atherosclerosis. We have recently generated caveolin-1-deficient [Cav-1(−/−)] mice in which caveolae organelles are completely eliminated from all cell types, except cardiac and skeletal muscle. In the present study, we examined the metabolism of cholesterol in wild-type (WT) and Cav-1(−/−) mouse embryonic fibroblasts (MEFs) and mouse peritoneal macrophages (MPMs). We observed that Cav-1(−/−) MEFs are enriched in esterified cholesterol but depleted of free cholesterol compared with their wild-type counterparts. Similarly, Cav-1(−/−) MPMs also contained less free cholesterol and were enriched in esterified cholesterol on cholesterol loading. In agreement with this finding, caveolin-1 deficiency was associated with reduced free cholesterol synthesis but increased acyl-CoA:cholesterol acyl-transferase (ACAT) activity. In wild-type MPMs, we observed that caveolin-1 was markedly upregulated on cholesterol loading. Despite these differences, cellular cholesterol efflux from MEFs and MPMs to HDL was not affected in the Cav-1-deficient cells. Neither ATP-binding cassette transporter G1 (ABCG1)- nor scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux was affected. Cellular cholesterol efflux to apolipoprotein A-I was not significantly reduced in Cav-1(−/−) MPMs compared with wild-type MPMs. However, ABCA1-mediated cholesterol efflux was clearly more sensitive to the inhibitory effects of glyburide in Cav-1(−/−) MPMs versus WT MPMs. Taken together, these findings suggest that caveolin-1 plays an important role in the regulation of intracellular cholesterol homeostasis and can modulate the activity of other proteins that are involved in the regulation of intracellular cholesterol homeostasis.

scholarly journals SULT2B1b inhibits reverse cholesterol transport and promotes cholesterol accumulation and inflammation in lymphocytes from AMI patients with low LDL-C levels

2020 ◽  
Vol 134 (2) ◽  
pp. 273-287
Author(s):  
Yanan Zhang ◽  
Zhongzhou Guo ◽  
Tongwei Wu ◽  
Jichen Liu ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Cpg Island ◽  
Cholesterol Content ◽  
Inflammatory Factors ◽  
Major Adverse Cardiovascular Events ◽  
Mrna Levels ◽  
Cholesterol Accumulation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Intracellular Cholesterol

Abstract The current main treatment for coronary artery disease (CAD) is to reduce low-density lipoprotein cholesterol (LDL-C) by statins, which could decrease the incidence of major adverse cardiovascular events (MACEs) by 30%. However, many residual risks still remain. To clarify the mechanism involved, we studied patients with acute myocardial infarction (AMI) with low LDL-C levels. Lymphocytes were isolated, and it was found that despite no difference in plasma LDL-C level, the lymphocyte cholesterol content was higher in AMI patient than those in non-CAD patients; thus, the decrease in intracellular cholesterol content was inconsistent with that in the plasma. Additionally, [3H]-cholesterol efflux rates were lower and mRNA levels of the inflammatory factors tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) higher in AMI lymphocytes. It was found that sulphotransferase 2B1b (SULT2B1b) expression was higher in AMI lymphocytes. Further research using Jurkat T lymphocytes confirmed that SULT2B1b knockdown increased cholesterol efflux capacity and decreased mRNA levels of TNF-α and IFN-γ by increasing liver X receptor (LXR)-β levels. Furthermore, the degree of CpG island methylation in the SULT2B1b promoter was reduced in cells from AMI patients. In conclusion, SULT2B1b up-regulation due to hypomethylation of its promoter promotes cholesterol accumulation and inflammation by inhibiting LXR-β in lymphocytes of AMI patients with low LDL-C levels. Therefore, reducing intracellular cholesterol is also important as plasma cholesterol levels. Therapeutic approaches to decrease SULT2B1b expression might be potentially beneficial for CAD prevention by decreasing intracellular cholesterol.

scholarly journals Macrophage free cholesterol content regulates apolipoprotein E synthesis.

1987 ◽  
Vol 262 (24) ◽  
pp. 11657-11662 ◽  
Author(s):  
T Mazzone ◽  
H Gump ◽  
P Diller ◽  
G S Getz
Keyword(s):  
Apolipoprotein E ◽  
Free Cholesterol ◽  
Cholesterol Content

Abstract 276: SR-BI Suppresses Apoptosis by Reducing Endoplasmic Reticulum Stress and Promoting Akt Activity in Macrophages

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Huan Tao ◽  
Patricia G Yancey ◽  
Sean S Davies ◽  
L Jackson Roberts ◽  
John L Blakemore ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Apolipoprotein E ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Free Cholesterol ◽  
Oxidized Ldl ◽  
Tunel Staining ◽  
Type I ◽  
Apoptotic Cells ◽  
Atherosclerotic Lesions

Objective: Macrophage apoptosis contributes to atherosclerotic plaque necrosis, inflammation, development and rupture. Scavenger receptor class B type I (SR-BI) is a key regulator of HDL metabolism and cellular cholesterol homeostasis. Here we examined the hypothesis that macrophage SR-BI modulates lipid-associated cellular stress and apoptosis. Methods and Results: In vitro cell apoptosis assays were performed in primary macrophages, and for in vivo evidence, we examined TUNEL staining of atherosclerotic lesions of LDLR -/- mice that were reconstituted with SR-BI -/- or WT bone marrow after 16 weeks on a Western diet. We found that SR-BI deficiency led to ~64.3% more apoptotic cells induced by oxidized LDL or free cholesterol in primary macrophages, and 6-fold more lesional apoptotic cells in SR-BI -/- →LDLR -/- mice compared to WT recipient mice. In macrophages, SR-BI deficiency caused significant accumulations of cellular free cholesterol and elevated markers of endoplasmic reticulum (ER) stress. These were exacerbated by feeding mice a high-cholesterol diet or inactivating the apolipoprotein E gene. Peroxidation of lipoproteins and cell membranes leads to modification of phosphatidylethanolamine by lipid aldehydes including isolevuglandins (IsoLG-PE). Treatment of macrophages with IsoLG-PE induced 52.6% more apoptotic cells in SR-BI -/- macrophages compared to WT. Transgenic expression of SR-BI by transfection of SR-BI -/- macrophages rescued oxidative stress-induced ER stress and cell apoptosis. SR-BI deficiency inhibited the Akt pathway compromising macrophage survival and increasing lesion necrosis. Moreover, Akt Activator was able to rescue SR-BI deficiency associated apoptosis in macrophages. Apolipoprotein E interacts with SR-BI in macrophages, co-operating for cellular lipid homeostasis and cell survival signaling. Conclusion: SR-BI protects against cell apoptosis induced by lipid stress in macrophages and atherosclerotic lesions. The underlying mechanisms are, at least in part, through reducing lipid-associated ER stress and promoting Akt activity in macrophages. Thus, we identify macrophage SR-BI-mediated apoptosis pathways as molecular targets for the prevention of atherosclerotic cardiovascular events.

Apolipoprotein A-I stimulates the transport of intracellular cholesterol to cell-surface cholesterol-rich domains (caveolae)

2001 ◽  
Vol 358 (1) ◽  
pp. 79-86 ◽  
Author(s):  
Dmitri SVIRIDOV ◽  
Noel FIDGE ◽  
Gabrielle BEAUMIER-GALLON ◽  
Christopher FIELDING
Keyword(s):  
Cell Surface ◽  
Cholesterol Efflux ◽  
Partial Purification ◽  
Cholesterol Transport ◽  
Dependent Manner ◽  
Cholesterol Trafficking ◽  
Apolipoprotein A ◽  
Intracellular Cholesterol ◽  
Plasma Apolipoprotein ◽  
Stimulation Of

We have studied the effect of lipid-free human plasma apolipoprotein A-I (apoA-I) on the transport of newly synthesized cholesterol to cell-surface cholesterol-rich domains, which in human skin fibroblasts are mainly represented by caveolae. Changes in transport of newly synthesized cholesterol were assessed after labelling cells with [14C]acetate at 15°C and warming cells to permit the transfer of cholesterol, followed by the selective oxidation of cholesterol in cholesterol-rich domains (caveolae) in the plasma membrane before their partial purification. ApoA-I, but not BSA added in an equimolar concentration, enhanced the transport of cholesterol to the caveolae up to 5-fold in a dose- and time-dependent manner. The effect of apoA-I on cholesterol transport exceeded its effect on cholesterol efflux, resulting in an accumulation of intracellular cholesterol in caveolae. Methyl-β-cyclodextrin, added at a concentration promoting cholesterol efflux to the same extent as apoA-I, also stimulated cholesterol trafficking, but was 3-fold less effective than apoA-I. Progesterone inhibited the transport of newly synthesized cholesterol to the caveolae. Treatment of cells with apoA-I stimulated the expression of caveolin, increasing the amount of caveolin protein and mRNA by approx. 2-fold. We conclude that apoA-I induces the transport of intracellular cholesterol to cell-surface caveolae, possibly in part through the stimulation of caveolin expression.

scholarly journals Intracellular cholesterol transporter StarD4 binds free cholesterol and increases cholesteryl ester formation

2008 ◽  
Vol 49 (7) ◽  
pp. 1409-1419 ◽  
Author(s):  
Daniel Rodriguez-Agudo ◽  
Shunlin Ren ◽  
Eric Wong ◽  
Dalila Marques ◽  
Kaye Redford ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Free Cholesterol ◽  
Ester Formation ◽  
Intracellular Cholesterol
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