Cholesterol Journal Articles

Record 10101 to 10120

Posttranslational regulation of acid sphingomyelinase in niemann-pick type C1 fibroblasts and free cholesterol-enriched chinese hamster ovary cells
Reagan, J. W., Jr., M. L. Hubbert, et al. (2000), J Biol Chem 275(48): 38104-10.
Abstract: Niemann-Pick type C disease is characterized by the accumulation of cholesterol and other lipids within the lysosomal compartment, a process that is often accompanied by a reduction in acid sphingomyelinase activity. These studies demonstrate that a CHO cell mutant (CT-60), which accumulates lysosomal cholesterol because of a defective NP-C1 protein, has approximately 5-10% of the acid sphingomyelinase activity of its parental cell line (25-RA) or wild type (CHO-K1) cells. The cholesterol-induced reduction in acid sphingomyelinase activity can be reproduced in CHO-K1 cells by incubation in the presence of low density lipoprotein (LDL) and progesterone, which impairs the normal egress of LDL-derived cholesterol from the lysosomal compartment. Kinetic analysis of sphingomyelin hydrolysis in cell extracts suggests that the CT60 cells have a reduced amount of functional acid sphingomyelinase as indicated by a 10-fold reduction in the apparent V(max). Western blot analysis using antibodies generated to synthetic peptides corresponding to segments within the carboxyl-terminal region of acid sphingomyelinase demonstrate that both the CT60 and the LDL/progesterone-treated CHO-K1 cells possess near normal levels of acid sphingomyelinase protein. Likewise, Niemann-Pick type C fibroblasts also displayed normal acid sphingomyelinase protein but negligible levels of acid sphingomyelinase activity. These data suggest that cholesterol-induced inhibition is a posttranslational event, perhaps involving cofactor mediated modulation of enzymatic activity or alterations in acid sphingomyelinase protein trafficking and maturation.

Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways
Hinson, D. D., K. L. Chambliss, et al. (1997), J Lipid Res 38(11): 2216-23.
Abstract: To assess the potential for feedback inhibition by isoprene intermediates in the cholesterol and nonsterol isoprene biosynthetic pathway, we expressed human cDNAs encoding mevalonate kinase (MKase), phosphomevalonate kinase (PMKase), and mevalonate diphosphate decarboxylase (MDDase) as fusion proteins in Escherichia coli DH5alpha, and purified these proteins by affinity chromatography. Several phosphorylated and non-phosphorylated isoprenes were analyzed as inhibitors of the enzymes using a standard spectrophotometric assay. Of the three proteins, only MKase was inhibited through competitive interaction at the ATP-binding site. The intermediates studied (and their relative inhibitory capacity) were: geranylgeranyl-diphosphate (GGPP, C20) > farnesyl-diphosphate (FPP, C15) > geranyl-diphosphate (GPP, C10) > isopentenyl-diphosphate (IPP, C5) > or = 3,3-dimethylallyl-diphosphate (DMAPP, C5) > farnesol (C15) > dolichol-phosphate (DP, C(80-100)). Mevalonate-diphosphate, geraniol, and dolichol were not inhibitors. Our data further define the spectrum of physiologic inhibitors of MKase, and provide the first evidence for feedback inhibition of MKase by a nonsterol isoprene produced by the branched pathway, dolichol-phosphate. These results provide additional evidence that MKase may occupy a central regulatory role in the control of cholesterol and nonsterol isoprene biosynthesis.

Postural change and within-day variation in total cholesterol and high-density lipoprotein-cholesterol levels
Miida, T., H. Sasaki, et al. (1996), Rinsho Byori 44(9): 860-4.
Abstract: To clarify whether the effect of the postural change on lipid levels can be corrected after the adjustment of albumin levels, and if so, whether there is within-day variation in corrected lipid levels, we measured total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and albumin levels before and after 60 min of the supine posture in 6 volunteers. We also measured the same variables before and after meals and at midnight in 30 inpatients with diabetes mellitus. We found that TC levels decreased by -7.7 +/- 2.7% (p < 0.005), and HDL-C by -5.8 +/- 5.3% (p < 0.05) after 60 min of the supine posture. The decreases disappeared after the adjustment of albumin to the baseline levels (TC; -0.2 +/- 1.0%, HDL-C; -1.7 +/- 4.2%, not significant). The within-day variation decreased from 10.9 +/- 4.9% to 5.8 +/- 2.2% in TC, and from 13.8 +/- 4.7% to 9.5 +/- 3.9% in HDL-C after the albumin adjustment. Corrected TC levels were, however, significantly lower after breakfast through at midnight than those before breakfast. This study indicates that the postural changes in lipid levels can be corrected after the adjustment of albumin levels, and that there is within-day variation in corrected TC levels. These findings suggest that the timing of sampling should be standardized for TC measurement in the management of diabetes mellitus with hypercholesterolemia.

Potencies of lipoproteins in fasting and postprandial plasma to accept additional cholesterol molecules released from cell membranes
Chung, B. H., F. Franklin, et al. (1998), Arterioscler Thromb Vasc Biol 18(8): 1217-30.
Abstract: To investigate the role of various lipoproteins in plasma to promote cholesterol efflux from cell membranes, potencies of lipoproteins in normolipidemic fasting and postprandial (PP) plasmas to accept additional cholesterol molecules from cell membranes were determined. We used red blood cells (RBCs) and lipoproteins in fresh blood as donors and acceptors of cell membrane cholesterol, respectively. When fresh fasting plasma (n=24) containing active lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer proteins (CETP) was incubated with a 3-fold excess of autologous RBCs at 37 degrees C for 18 hours, plasma cholesterol levels increased by 19.6% (38.5+/-14.2 mg/dL) owing to an exclusive increase in the CE level. Very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) fractions retained 48.1%, 26.3%, and 25.6% of the net cholesterol mass increase in fasting plasma, resulting in 91%, 8%, and 21% increases in their cholesterol contents, respectively. The PP plasma was 1.3-fold more potent than fasting plasma in promoting cholesterol efflux from RBCs by associating excess cholesterol with chylomicrons, resulting in a 356% increase in the cholesterol content of chylomicrons. These increases in lipoprotein cholesterol content indicate that chylomicrons were about 3.9x, 44x, and 17x more potent than fasting VLDL, LDL, and HDL, respectively, in accepting additional cholesterol molecules released from RBCs. The capacity of PP plasma to promote cholesterol efflux from RBCs was significantly correlated with plasma cholesterol levels (r=0.60, P<0.005), triglycerides (r=0.68, P<0.001), chylomicrons (r=0.90, P<0.001), VLDL (r=0.65, P<0.001), and LDL (r=0.47, P<0.025) but not with the levels of HDL (r= -0.34, P<0.20). In fasting plasma containing a low level of VLDL and HDL, isolated chylomicrons supplemented to the plasma were approximately 9x more potent than HDL in boosting the capacity of plasma to promote cholesterol efflux from RBCs. This study indicates that chylomicrons in PP plasma are the most potent ultimate acceptors of cholesterol released from cell membranes and that a low HDL level is not a factor that limits the ability of PP plasma to promote cholesterol efflux from cell membranes. Our data obtained from an in-vitro system suggest that PP chylomicrons may play a major role in promoting reverse cholesterol transport in vivo, since the transfer of cholesterol from cell membranes to chylomicrons will lead to the rapid removal of this cholesterol by the liver. HDL in vivo may promote reverse cholesterol transport by enhancing the rapid removal of chylomicrons from the circulation, since the rate of clearance of chylomicrons is positively correlated with the HDL level in plasma.

Potent hypocholesterolemic activity of the yeast Kluyveromyces marxianus YIT 8292 in rats fed a high cholesterol diet
Yoshida, Y., W. Yokoi, et al. (2004), Biosci Biotechnol Biochem 68(6): 1185-92.
Abstract: The hypocholesterolemic activities of 81 yeast strains were examined in rats fed a high cholesterol diet (HCD). Male Wistar rats were fed an HCD or an HCD supplemented with 10% yeast for 7 d. It was found that the hypocholesterolemic activities of the yeasts varied remarkably between strains. Kluyveromyces marxianus YIT 8292 exhibited the most potent hypocholesterolemic activity among the yeasts that were tested. K. marxianus YIT 8292 significantly decreased not only plasma total cholesterol but also liver total cholesterol when administered as a dietary admixture at a concentration of 3%. In contrast, brewer's yeast and baker's yeast, which have been predominantly used for food, did not exhibit hypocholesterolemic activity even when administered at a concentration of 10%. These results suggest that K. marxianus YIT 8292 may be utilized as a novel food material with the ability to contribute to the prevention of hypercholesterolemia.

Potent inhibitors of acyl-CoA:cholesterol acyltransferase. Structure-activity relationships of novel N-(4-oxochroman-8-yl)amides
Kataoka, K., T. Shiota, et al. (1995), J Med Chem 38(16): 3174-86.
Abstract: Novel N-(4-oxochroman-8-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) in vitro and to lower serum total cholesterol in cholesterol-fed rats in vivo. Among the synthesized compounds, N-(7-alkoxy-4-oxochroman-8-yl)amide derivatives showed potent ACAT inhibitory activity both in vitro and in vivo. The structure-activity relationships of these N-(4-oxochroman-8-yl)amides and related compounds are discussed on the basis of these two assays. The carbonyl group at position 4 of the 4-chromanone was essential for potent ACAT inhibitory activity. N-(Chromon-8-yl) derivatives were less potent than N-(4-oxochroman-8-yl) derivatives. An alkoxy group at position 7 of the 4-chromanone moiety was important for potent ACAT inhibitory activity. In the N-(7-alkoxy-4-oxochroman-8-yl)amide derivatives, another necessary factor to elicit the potent ACAT inhibitory activity was lipophilicity of the molecules. The highly lipophilic acid amides N-(7-methoxy-4-oxochroman-8-yl)-2,2-dimethyldodecanamide (35) and 4-6-(4-chlorophenoxy)hexyloxy-N-(7-methoxy-4-oxochroman-8- yl)benzamide (63) showed potent activity. Introduction of a highly lipophilic alkoxy group at position 7 of the 4-chromanone moiety instead of methoxy group also resulted in potent activity. In this case, highest inhibitory activity was obtained by N-7-(decyloxy)-4-oxochroman-8-yl-2,2-dimethylpropanamid e (65). The most potent compound, N-(7-methoxy-4-oxochroman-8-yl)-2,2-dimethyldodecanamide (35, TEI-6522), showed significant ACAT inhibitory activity (rabbit small intestine IC50 = 13 nM, rabbit liver IC50 = 16 nM), foam cell formation inhibitory activity (rat peritoneal macrophage IC50 = 160 nM), and extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (61% at a dose of 0.1 mg/kg/day po).

Potent, selective, and systemically-available inhibitors of acyl-coenzyme A:cholesterol acyl transferase (ACAT)
McCarthy, P. A., E. S. Hamanaka, et al. (1994), J Med Chem 37(9): 1252-5.

Potential effect of cyclosporin A in formation of cholesterol gallstones in pediatric liver transplant recipients
Cao, S., K. Cox, et al. (1997), Dig Dis Sci 42(7): 1409-15.
Abstract: Recent advancements in liver transplantation have resulted in extended survival both for grafts and recipients. Such improvement, together with the shortage of donor organs has prompted expansion of the donor pool to include less than ideal donors, especially in life-threatening situations. The use of older liver donors has been associated with lower long-term survival. However, potential morbidity such as gallstone formation has not been explored. We analyzed bile composition in a child who developed cholesterol gallstones in the proximal bile duct two years after undergoing emergency liver transplantation with a liver from a 78-year-old donor. Oral administration of ursodeoxycholic acid (ursodiol) shifted the cholesterol composition of the bile from a supersaturated, potentially crystallized state to a liquid (micellar) state. Unlike cyclosporin A, FK506 showed an increase in the proportion of chenodeoxycholic acid and a decrease in the proportion of cholic acid, and thus may exhibit minimal or no hepatotoxic effect. Thus, in donor livers with factors known to be associated with cholesterol gallstone formation (such as age, sex, or obesity), one may consider analyzing the bile composition at the time of procurement. Depending on cholesterol and bile acid composition the use of FK506 with or without addition of ursodeoxycholic acid may be warranted.

Potential for increasing high-density lipoprotein cholesterol, subfractions HDL2-C and HDL3-C, and apoprotein AI among middle-age women
Meilahn, E. N., L. H. Kuller, et al. (1991), Prev Med 20(4): 462-73.
Abstract: BACKGROUND. Studies have shown high-density lipoprotein cholesterol (HDL-C) to be a strong predictor of cardiovascular disease (CVD) risk. METHODS. Determinants of HDL-C and apoprotein AI concentrations were evaluated cross-sectionally in 1987 among 429 women, ages 45-54, from a population-based study of CVD risk factors through menopause (the Healthy Women Study, University of Pittsburgh). RESULTS. Subjects were healthy and not taking hormone replacement therapy. Results showed levels of HDL-C (mg/dl) to range from 23 to 117, HDL2-C from 0 to 53, HDL3-C from 16 to 66, and apoprotein AI from 87 to 204. Multivariate analyses which included age, cigarettes/day, alcohol intake (g/day), physical activity (Paffenbarger questionnaire), body mass index (BMI), and waist/hip ratio (WHR) showed that women who smoked greater than or equal to 20 cigarettes a day, reported little or no alcohol intake, expended less than 500 kcal/week, and were in the highest quintile of BMI and WHR had, on average, 33 mg/dl lower HDL-C than slender, nonsmoking women who drank moderately and exercised. HDL2-C showed a similar pattern, whereas the HDL3-C concentration had only a modest association with these factors. HDL-C was somewhat lower among women who had stopped menstruating than among premenopausal women. The apoprotein AI level was associated with alcohol intake (positively) and BMI (negatively). CONCLUSION. Theoretically, by raising their HDL-C by 10 mg/dl, women could reduce their CVD risk by as much as one-third (based on results from the Framingham Heart Study). As CVD is the leading cause of death among postmenopausal women, the potential impact of such a reduction in risk would be large.

Potential gene therapy for lecithin-cholesterol acyltransferase (LCAT)-deficient and hypoalphalipoproteinemic patients with adenovirus-mediated transfer of human LCAT gene
Seguret-Mace, S., M. Latta-Mahieu, et al. (1996), Circulation 94(9): 2177-84.
Abstract: BACKGROUND: Overexpression of human lecithin-cholesterol acyltransferase (LCAT) in transgenic mice results in an increase of the antiatherogenic HDLs. METHODS AND RESULTS: To investigate the potential use of LCAT for gene therapy, a recombinant adenovirus was constructed in which the human LCAT cDNA was expressed under the control of the human cytomegalovirus immediate/early promoter followed by a chimeric intron (AdCMV human LCAT). Human apolipoprotein (apo) A-I transgenic mice infected with AdCMV human LCAT by intravenous injection accumulated reactive LCAT in the plasma. LCAT activity was increased 201-fold in the plasma of mice infected with 1 x 10(6) pfu AdCMV human LCAT, from 45 +/- 2 to 9068 +/- 812 nmol.mL-1.h-1, in comparison with basal LCAT activity measured in control mice, 5 days after injection. Plasma HDL cholesterol levels rose from 117 +/- 12 to 797 +/- 48 mg/dL, and plasma human apo A-I concentrations increased from 247 +/- 14 to 616 +/- 17 mg/dL, in AdCMV human LCAT infected mice compared with control mice. HDL particles were larger and had a different electrophoretic mobility. Studies of cholesterol efflux by incubation of serum with cholesterol-loaded Fu5AH cells showed that serum from AdCMV human LCAT-infected mice promoted a significantly higher efflux than did that of the controls. CONCLUSIONS: These data establish the potential of this approach for treatment of subjects with LCAT gene defects as well as patients with low plasma levels of apo A-I and HDL cholesterol.

Potential influence of timing of low-density lipoprotein cholesterol evaluation in patients with acute coronary syndrome
Faulkner, M. A., D. E. Hilleman, et al. (2001), Pharmacotherapy 21(9): 1055-60.
Abstract: OBJECTIVE: To determine the significance of timing of low-density lipoprotein (LDL) cholesterol evaluation in patients with chest pain as it relates to subsequent National Cholesterol Education Program (NCEP) treatment decisions. DESIGN: Prospective, observational study. SETTING: A university-affiliated tertiary care hospital. PATIENTS: Sixty-two patients with coronary heart disease who were not receiving lipid-lowering therapy and whose LDL levels were obtained 25-48 hours after onset of chest pain. INTERVENTION: We evaluated laboratory test results of patients with chest pain admitted to the cardiac care unit to determine risk to patients when LDL levels obtained inappropriately are used to make decisions regarding antihyperlipidemic therapy. MEASUREMENTS AND MAIN RESULTS: Inpatient and outpatient LDL levels were compared, and changes in NCEP treatment decisions analyzed. Differences between inpatient and outpatient LDL levels were significant (p<0.05), which frequently resulted in changes in therapy using the NCEP guidelines. The LDL levels of most inpatients were consistent with NCEP goals for patients with coronary heart disease, whereas the outpatient levels showed a need for drug therapy. CONCLUSION: Lipid values obtained 25-48 hours after hospital admission in patients with acute coronary syndromes do not represent baseline values and may significantly alter the treatment approach; thus, they should not be used to direct drug therapy.

Potential problems in the use of commercial preparations of radiolabeled cholesterol
Mahlberg, F. H., A. Rodriguez-Oquendo, et al. (1990), Atherosclerosis 84(2-3): 95-100.
Abstract: Through a series of biological and analytical procedures, we demonstrate that a compound purchased from a commercial supplier as 7-3Hcholesterol was not cholesterol. In mouse peritoneal macrophages, this compound was metabolized differently than other radiolabeled cholesterol preparations and was accumulated in the steryl ester pool. In contrast, Fu5AH rat hepatoma cells did not discriminate this compound from cholesterol. Further analysis of the anomalous 7-3Hcholesterol by TLC after cholesterol oxidase treatment and by HPLC indicated that this radiochemical was less polar than cholesterol standard and other radiolabeled cholesterol preparations tested. Mass spectrometry analysis disclosed that the chemical has a similar fragmentation pattern and the same molecular weight (386) as cholesterol.

Potential role of cholesterol in distinguishing malignant from benign pleural effusion
Plavec, G., I. Tomic, et al. (2004), Vojnosanit Pregl 61(6): 607-11.
Abstract: Cholesterol and carcinoembryonic antigen (CEA) levels in pleural effusion and sera, were measured in 199 patients with pleural effusions of various origins. Malignant cause was found in 93, and nonmalignant in 106 patients. Mean cholesterol level in sera of patient with malignant disease was 5.0 +/- 0.93 mmol/L, and in nonmalignant group 4.34 +/- 1.32 mmol/L. The difference was not statistically significant. Mean cholesterol level in nonmalignant pleural effusions was higher thAn those in malignant (2.51 +/- 1.23 mmol/L; and 2.28 +/- 1.06 mmol/L), but the difference was also not significant. Average pleural fluid/serum cholesterol ratio (Holl/S) in nonmalignant group was 0.61 +/- 0.32 and in malignant group 0.46 +/- 0.22. The difference between those mean values was significant. Higher ratio, at the cut off value of 0.5 was found in 79/106 and in 25/93 malignant patients. Calculated sensitivity was 75%, specificity 73%, positive predictive value 76%, negative predictive value 65% and accuracy 69%. Significant negative correlation between Holi/S and pleural fluid CEA was found (p < 0.05). It was assumed that pleural fluid/serum cholesterol ratio lower than 0.5 could be of great benefit, as an additional test in the differentiation of malignant from benign pleural effusion.

Potentiation by cholesterol and vitamin D3 oxygenated derivatives of arachidonic acid release and prostaglandin E2 synthesis induced by the epidermal growth factor in NRK 49F cells: the role of protein kinase C
Astruc, M. E. and Z. Lahoua (1994), Cell Signal 6(7): 763-75.
Abstract: We have previously demonstrated that oxysterols and calcitriol potentiate arachidonic acid (AA) release and prostaglandin (PG) synthesis when NRK cells (fibroblastic clone 49F) are activated by foetal calf serum. As serum is essential for a full oxysterol effect, we hypothesized that these compounds could act on one or more of the events triggered by serum growth factor binding to their specific receptors and leading to PLA2 activation; we showed that the oxysterol effect on AA release is synergistic with, but not fully dependent on, protein kinase C (PKC) activity and Ca2+ ion fluxes, suggesting that oxysterols could effect early events in the cell signalling pathway. In the present paper, we investigated the effect of some oxysterols and calcitriol on epidermal growth factor (EGF)-induced AA release and PGE2 synthesis in NRK cells. The clear potentiation of EGF effect by most of the oxygenated sterols--chiefly when polyoxidized--cannot be explained by a modification of EGF high affinity binding site number which was only moderately increased after a 4 h incubation of cells with these compounds, and moreover was not related to the ability of a given oxysterol to increase PLA2 activity; whatever the compound, the dissociation constant (Kd) of either a high or low affinity binding site was unchanged (respectively, 3.5 x 10(-11) M and 4.4 x 10(-10) M). Genistein, a known inhibitor of EGF receptor tyrosine kinase, changed neither the EGF effect on AA release nor its potentiation by oxysterol, whereas it inhibited PGE2 synthesis in both situations. PKC activation by phorbol ester TPA increased the effect of EGF alone as well as the oxysterol potentiating effect, whereas PKC down-regulation strongly decreased both of these effects, showing that both are dependent on PKC activity. Nevertheless staurosporine, a PKC inhibitor, did not reproduce the effects of PKC down-regulation on EGF activation: stimulatory when AA release was induced by EGF alone, inhibitory when AA release is induced by TPA alone, this compound did not modify the oxysterol potentiating effect. In conclusion, the potentiating effect of oxysterols on AA release seems to be exerted downstream to the growth factor receptor (as demonstrated here with EGF) and probably at the PKC level, but not exclusively.

Potentiation of beta-adrenoceptor agonist mediated-lipolysis by cholesterol-derived oxysterols
Lau, W. F., H. E. Khoo, et al. (1995), Biochem Mol Biol Int 35(6): 1349-58.
Abstract: Cholesterol-derived oxysterols such as cholestanol, cholestanone and coprostanone were able to potentiate epinephrine-induced lipolysis in intact rat adipocytes but not cholesterol. The relative potency of the oxysterols followed the sequence: cholestanone > or = coprostanone > cholestanol. Cholestanone was selected to study its mode of action on epinephrine-induced lipolysis. A sustained increase in the level of cAMP was observed in adipocytes incubated with both cholestanone and epinephrine compared to a transient peaking of cAMP in adipocytes incubated with epinephrine alone. Binding assays using 125Icyanopindolol (beta-adrenergic receptor antagonist) showed that cholestanone could increase the binding affinity of 125I-cyanopindolol to beta-adrenergic receptors on rat adipocyte ghost membranes without affecting the total number of binding sites. The results suggest that cholestanone exerts its potentiation effect by facilitating the binding of beta-adrenergic agonist to its receptor.

Potpourri: effects of unsaturation on lipid structure; plasma cholesterol ester and lipid-transfer proteins; and cholesterol-sensing proteins and cellular cholesterol movement
Small, D. M. (1998), Curr Opin Struct Biol 8(4): 413-6.

PPAR agonists protect mesangial cells from interleukin 1beta-induced intracellular lipid accumulation by activating the ABCA1 cholesterol efflux pathway
Ruan, X. Z., J. F. Moorhead, et al. (2003), J Am Soc Nephrol 14(3): 593-600.
Abstract: Previous studies have demonstrated that inflammatory cytokines such as interleukin-1beta (IL-1beta) promote lipid accumulation in human mesangial cells (HMC) by dysregulating the expression of lipoprotein receptors. Intracellular lipid accumulation is governed by both influx and efflux; therefore, the effect of IL-1beta on the efflux of lipid from HMC was investigated. IL-1beta was shown to inhibit (3)H-cholesterol efflux from HMC and increase total intracellular cholesterol concentration, probably as a result of reduced expression of the adenosine triphosphate (ATP) binding cassette A1 (ABCA1), a transporter protein involved in apolipoprotein-A1 (apo-A1)-mediated lipid efflux. To ascertain the molecular mechanisms involved, expression of peroxisome proliferator-activated receptors (PPAR) and liver X receptoralpha (LXRalpha) were examined. IL-1beta (5 ng/ml) reduced PPARalpha, PPARgamma, and LXRalpha mRNA expression. Activation of PPARgamma with the agonist prostaglandin J2 (10 micro M) and of PPARalpha with either bezafibrate (100 micro M) or Wy14643 (100 micro M) both increased LXRalpha and ABCA1 gene expression also and enhanced apoA1-mediated cholesterol efflux from lipid-loaded cells, even in the presence of IL-1beta. A natural ligand of LXRalpha, 25-hydroxycholesterol (25-OHC), had similar effects; when used together with PPAR agonists, an additive effect was observed, indicating co-operation between PPAR and LXRalpha in regulating ABCA1 gene expression. This was supported by the observation that overexpression of either PPARalpha or PPARgamma by transfection enhanced LXRalpha and ABCA1 gene induction by PPAR agonists. Taken together with previous data, it appears that, in addition to increasing lipid uptake, inflammatory cytokines promote intracellular lipid accumulation by inhibiting cholesterol efflux through the PPAR-LXRalpha-ABCA1 pathway. These results suggest potential mechanisms whereby inflammation may exacerbate lipid-mediated cellular injury in the glomerulus and in other tissues and indicate that PPAR agonists may have a protective effect.

PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway
Chinetti, G., S. Lestavel, et al. (2001), Nat Med 7(1): 53-8.
Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.

PPARgamma regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1
Chui, P. C., H. P. Guan, et al. (2005), J Clin Invest 115(8): 2244-56.
Abstract: In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARgamma dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARgamma ligand treatment in vivo. Serum oxLDL levels are decreased in both lean and obese diabetic animals treated with TZDs. These data identify OLR1 as a novel PPARgamma target gene in adipocytes. While the physiological role of adipose tissue in cholesterol and oxLDL metabolism remains to be established, the induction of OLR1 is a potential means by which PPARgamma ligands regulate lipid metabolism and insulin sensitivity in adipocytes.

Practice guidelines and cholesterol policy
Garber, A. M. and J. L. Wagner (1991), Health Aff (Millwood) 10(2): 52-66.

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