| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Human apolipoprotein A-IV binds to apolipoprotein A-I/A-II receptor sites and promotes cholesterol efflux from adipose cells Steinmetz, A., R. Barbaras, et al. (1990), J Biol Chem 265(14): 7859-63. Abstract: Cholesterol efflux was studied in cultured mouse adipose cells after preloading with low density lipoprotein cholesterol. Exposure to complexes containing human apolipoprotein A-IV and L-alpha-dimyristoylphosphatidylcholine (DMPC) as well as to human lipoprotein particles containing apolipoprotein A-IV but not apolipoprotein A-I and particles containing apolipoproteins A-IV and A-I showed that both artificial and native apolipoprotein A-IV-containing particles were able to promote cholesterol efflux at 37 degrees C as a function of time and concentration. The half-maximal concentration was found to be 0.3 X 10(-6) M for apolipoprotein A-IV.DMPC complexes. Binding experiments performed in intact cells at 4 degrees C with labeled apolipoprotein A-IV.DMPC complexes showed the existence of specific binding sites, with a Kd value of 0.32 x 10(-6) M and a maximal binding capacity of 223,000 sites/cell. By cross-competition experiments with labeled and unlabeled complexes containing apolipoprotein A-IV, A-I, or A-II, it appeared that all three apolipoproteins bind to the same cell-surface recognition sites. It is suggested that apolipoprotein A-IV, which is present in the interstitial fluid surrounding adipose cells in vivo at concentrations similar to those required in vitro for the promotion of cholesterol efflux, plays a critical role in cholesterol removal from peripheral cells. |
| Human apolipoproteins A-I and A-II in cell cholesterol efflux: studies with transgenic mice Chiesa, G., C. Parolini, et al. (1998), Arterioscler Thromb Vasc Biol 18(9): 1417-23. Abstract: The first step in reverse cholesterol transport is the movement of cholesterol out of cells onto lipoprotein acceptors in the interstitial fluid. The contribution of specific lipoprotein components to this process remains to be established. In this study, the role of human apolipoproteins (apo) A-I and A-II in the efflux of cellular cholesterol was investigated in transgenic mouse models in which the expression of murine apoA-I was abolished due to gene targeting (A-IKO). Serum from A-IKO mice and from mice expressing human apoA-I and/or human apoA-II was incubated with 3Hcholesterol-labeled Fu5AH rat hepatoma cells for 4 hours at 37 degrees C. The cholesterol efflux to the serum of A-IKO mice was markedly lower than that to the serum of mice transgenic for human apoA-I (5.0 +/- 1.5% versus 25.0 +/- 4.0%). Expression of human apoA-II alone did not modify the cholesterol efflux capacity of A-IKO mouse serum. Cholesterol efflux to serum of mice expressing human apoA-II together with human apoA-I was significantly lower than that to human apoA-I mouse serum (20.0 +/- 2.3% versus 25.0 +/- 4.0%). Regression analysis of cholesterol efflux versus the lipid/apolipoprotein concentrations of mouse serum suggested that 3 independent factors contribute to determine the cholesterol efflux potential of serum: the apolipoprotein composition of HDL, the serum concentration of HDL phospholipids, and the presence of a small fraction of particles containing apoA-I. |
| Human ATP-binding cassette transporter-2 (ABCA2) positively regulates low-density lipoprotein receptor expression and negatively regulates cholesterol esterification in Chinese hamster ovary cells Davis, W., Jr., J. T. Boyd, et al. (2004), Biochim Biophys Acta 1683(1-3): 89-100. Abstract: We present evidence that the ATP binding-cassette transporter-2 (ABCA2) is a sterol-responsive gene that has a role in the trafficking of low-density lipoprotein-derived free cholesterol (LDL-FC). In HepG2 cells ABCA2 was coordinately expressed with other sterol-responsive genes. Stable constitutive expression of ABCA2 in Chinese hamster ovary cells (CHOA2) was accompanied by an increase the expression of the low-density lipoprotein receptor (LDLR) and other genes involved in the regulation of cholesterol homeostasis. LDLR mRNA was elevated greater than ninefold and 3-hydroxy-3-methylglutaryl CoA synthase (HMGCoA S) expression was elevated sevenfold in CHOA2 cells. The increase in LDLR expression was regulated at the level of transcription; however, culture of CHO and CHOA2 cells in medium containing lipoprotein-deficient serum (LPDS) results in similar levels of LDLR promoter expression. No differences were measured in the dose-dependent uptake of fluorescently labeled 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchorate-LDL (DiI-LDL) between CHO and CHOA2 cells cultured in medium containing LPDS. Ultraviolet microscopy revealed a similar distribution of the DiI-LDL label in cytoplasmic vesicles. We measured an LDL dose-dependent reduction in esterification of LDL-FC in intact CHOA2 cells cultured in medium containing LPDS, however, no significant difference was measured in acylcoenzyme A:cholesterol acyltransferase (ACAT) activity in cell-free extracts of CHO and CHOA2 cells. CHO cells or CHOA2 cells treated with the hydrophobic amine, U18666A, showed similar filipin staining of unesterified cholesterol in cytoplasmic vesicles. Addition of progesterone or U18666A to CHO cells elevated ABCA2 expression. Finally, we found that ABCA2 expression was elevated in Niemann-Pick type C1 (NPC1) fibroblasts and in Familial Hypercholesterolemia (FHC) fibroblasts. |
| Human breath isoprene and its relation to blood cholesterol levels: new measurements and modeling Karl, T., P. Prazeller, et al. (2001), J Appl Physiol 91(2): 762-70. Abstract: Numerous publications have described measurements of breath isoprene in humans, and there has been a hope that breath isoprene analyses could be a noninvasive diagnostic tool to assess blood cholesterol levels or cholesterol synthesis rate. However, significant analytic problems in breath isoprene analysis and variability in isoprene levels with age, exercise, diet, etc., have limited the usefulness of these measurements. Here, we have applied proton transfer reaction-mass spectrometry to this problem, allowing on-line detection of breath isoprene. We show that breath isoprene concentration increases within a few seconds after exercise is started as a result of a rapid increase in heart rate and then reaches a lower steady state when breath rate stabilizes. Additional experiments demonstrated that increases in heart rate associated with standing after reclining or sleeping are associated with increased breath isoprene concentrations. An isoprene gas-exchange model was developed and shows excellent fit to breath isoprene levels measured during exercise. In a preliminary experiment, we demonstrated that atorvastatin therapy leads to a decrease in serum cholesterol and low-density-lipoprotein levels and a parallel decrease in breath isoprene levels. This work suggests that there is constant endogenous production of isoprene during the day and night and reaffirms the possibility that breath isoprene can be a noninvasive marker of cholesterologenesis if care is taken to measure breath isoprene under standard conditions at constant heart rate. |
| Human CD59 is a receptor for the cholesterol-dependent cytolysin intermedilysin Giddings, K. S., J. Zhao, et al. (2004), Nat Struct Mol Biol 11(12): 1173-8. Abstract: Cholesterol is believed to serve as the common receptor for the cholesterol-dependent cytolysins (CDCs). One member of this toxin family, Streptococcus intermedius intermedilysin (ILY), exhibits a narrow spectrum of cellular specificity that is seemingly inconsistent with this premise. We show here that ILY, via its domain 4 structure, binds to the glycosyl-phosphatidylinositol-linked membrane protein human CD59 (huCD59). CD59 is an inhibitor of the membrane attack complex of human complement. ILY specifically binds to huCD59 via residues that are the binding site for the C8alpha and C9 complement proteins. These studies provide a new model for the mechanism of cellular recognition by a CDC. |
| Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype Pullinger, C. R., C. Eng, et al. (2002), J Clin Invest 110(1): 109-17. Abstract: Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. The CYP7A1 gene encodes the enzyme cholesterol 7alpha-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder. |
| Human cholesterol synthesis measurement using deuterated water. Theoretical and procedural considerations Jones, P. J., C. A. Leitch, et al. (1993), Arterioscler Thromb 13(2): 247-53. Abstract: Human cholesterogenesis is measurable as the rate of incorporation of deuterium derived from deuterium oxide (D2O) within the body water pool into plasma or erythrocyte cholesterol pools. Oral D2O equilibrates across body water, thus enabling extracellular sampling of pools (such as urine) to serve as accurate indicators of intracellular deuterium enrichments at the point of synthesis. Required doses of D2O fall below the threshold associated with negative side effects. Deuterium/carbon incorporation ratios into cholesterol during biosynthesis have been established that are applicable in humans. Models using unconstrained and constrained curve fitting permit improved flexibility in interpretation of deuterium-uptake kinetics. However, sample-size restrictions presently limit the ability of the technique to examine the kinetics within individual lipoprotein species. Correction of enrichment data for proton exchange during combustion and reduction phases of sample preparation is an additional important procedural concern. In summary, the deuterated-water procedure is a useful tool in studies of human cholesterol synthesis that offers the advantages of short measurement interval, relative noninvasiveness, and provision of a direct index of synthesis in comparison with other available techniques. |
| Human cholesteryl ester transfer protein gene proximal promoter contains dietary cholesterol positive responsive elements and mediates expression in small intestine and periphery while predominant liver and spleen expression is controlled by 5'-distal sequences. Cis-acting sequences mapped in transgenic mice Oliveira, H. C., R. A. Chouinard, et al. (1996), J Biol Chem 271(50): 31831-8. Abstract: The plasma cholesteryl ester transfer protein (CETP) facilitates the transfer of high density lipoprotein cholesteryl esters to other lipoproteins and appears to be a key regulated component of reverse cholesterol transport. Earlier studies showed that a CETP transgene containing natural flanking sequences (-3.4 kilobase pairs (kbp) upstream, +2.2 kbp downstream) was expressed in an authentic tissue distribution and induced in liver and other tissues in response to dietary or endogenous hypercholesterolemia. In order to localize the DNA elements responsible for these effects, we prepared transgenic mice expressing six new DNA constructs containing different amounts of natural flanking sequence of the CETP gene. Tissue-specific expression and dietary cholesterol response of CETP mRNA were determined. The native pattern of predominant expression in liver and spleen with cholesterol induction was shown by a -3.4 (5'), +0.2 (3') kbp transgene, indicating no major contribution of distal 3'-sequences. Serial 5'-deletions showed that a -570 base pairs (bp) transgene gave predominant expression in small intestine with cholesterol induction of CETP mRNA in that organ, and a -370 bp transgene gave highest expression in adrenal gland with partial dietary cholesterol induction of CETP mRNA and plasma activity. Further deletion to -138 bp 5'-flanking sequence resulted in a transgene that was not expressed in vivo. Both the -3.4 kbp and -138 bp transgenes were expressed when transfected into a cultured murine hepatocyte cell line, but only the former was induced by treating the cells with LDL. When linked to a human apoA-I transgene, the -570 to -138 segment of the CETP gene promoter gave rise to a relative positive response of hepatic apoA-I mRNA to the high cholesterol diet in two out of three transgenic lines. Thus, 5'-elements between -3,400 and -570 bp in the CETP promoter endow predominant expression in liver and spleen. Elements between -570 and -370 are required for expression in small intestine and some other tissues, and elements between -370 and -138 contribute to adrenal expression. The minimal CETP promoter element associated with a positive sterol response in vivo was found in the proximal CETP gene promoter between -370 and -138 bp. This region contains a tandem repeat of a sequence known to mediate sterol down-regulation of the HMG-CoA reductase gene, suggesting either the presence of separate positive and negative sterol response elements in this region or the use of a common DNA element for both positive and negative sterol responses. |
| Human gallbladder mucosal function. Effect of concentration and acidification of bile on cholesterol and calcium solubility Shiffman, M. L., H. J. Sugerman, et al. (1990), Gastroenterology 99(5): 1452-9. Abstract: The most recognized function of the human gallbladder is to store bile. However, this organ is not a static reservoir. It actively modifies bile by two processes: concentration and acidification. This study was designed to simultaneously evaluate the relationship between these two physiological processes in the normal human gallbladder and to define their effects on biliary cholesterol and calcium solubility. Bile was sampled directly from the gallbladder of 78 morbidly obese patients undergoing elective gastric bypass procedures. All had negative results of intra-operative ultrasound examinations for sludge and gallstones, normal liver function tests, and no history of hepatobiliary disease. Bile salt concentrations, an indirect index of concentration by the gallbladder, ranged from 15.1-272.8 mmol/L. As bile salt increased, Na+, K+, free Ca2+, cholesterol, phospholipid, and total lipid increased linearly; Cl-1 decreased linearly. Molar percent cholesterol decreased from 17.2% in dilute bile to 10.1% in fully concentrated bile, suggesting that cholesterol was absorbed by the gallbladder. As bile was concentrated, cholesterol saturation index decreased curvilinearly from a maximum of 3.7 in dilute bile to 1.0-1.5 in concentrated bile. Concentration of gallbladder bile was accompanied by progressive acidification. Bile pH decreased linearly with increasing bile salt; CO3(2-) decreased curvilinearly. Despite increasing Ca2+, CaCO3 saturation index decreased curvilinearly with increasing bile salt from a maximum of 3.62 in dilute bile to a minimum of 0.12 in concentrated and acidified bile. CaCO3 saturation index also decreased exponentially with decreasing pH. This study concludes that concentration of bile enhances cholesterol solubility while acidification enhances calcium salt solubility. By increasing the solubilities of these two species, gallbladder mucosal function may play a key role in preventing gallstone formation. |
| Human G-protein beta3 subunit variant is associated with serum potassium and total cholesterol levels but not with blood pressure Ishikawa, K., Y. Imai, et al. (2000), Am J Hypertens 13(2): 140-5. Abstract: The activity of a sodium-proton exchanger is enhanced in the patients with essential hypertension and regulated via G-protein, which is a signal transducer between receptors and intracellular effectors. A recent study has revealed that a novel variant (C825T) in exon 10 of the gene encoding the beta3 subunit of heterotrimetric G proteins (GNB3) is a genetic factor predisposing to hypertension in Caucasians. We examined the association between GNB3/ C825T and blood pressure, lipids, electrolytes, and other parameters in a Japanese population. Subjects (n = 352) were selected from the Ohasama Study, the population of which is regarded as from a rural community in Japan. To obtain precise clinical measurements, 24-h ambulatory blood pressure monitoring (ABPM), brain magnetic resonance imaging (MRI), and carotid ultrasonography (CUS) were conducted in this population. In addition, we recruited 762 subjects from outpatients at the Osaka University Medical School to carry out the association study between hypertension and GNB3. The GNB3 genotype distribution did not differ significantly between normotensives and hypertensives in either of the two studies. The T825 allele of GNB3 was not associated with the presence of hypertension, blood pressure level, the number of brain lacunae or carotid wall thickness. However, the serum potassium and total cholesterol levels were significantly higher in subjects with the T allele (P <.005). The T825 allele of GNB3 is associated with increased serum potassium and total cholesterol levels but not with blood pressure in a Japanese population. |
| Human granulocyte-macrophage colony-stimulating factor lowers the levels of plasma cholesterol with an increase in mRNA for very low density lipoprotein receptor in rabbits Ishibashi, T., K. Yokoyama, et al. (1995), Ann N Y Acad Sci 748: 630-3. |
| Human granulosa cells use high density lipoprotein cholesterol for steroidogenesis Azhar, S., L. Tsai, et al. (1998), J Clin Endocrinol Metab 83(3): 983-91. Abstract: This study examines the ability of human high density lipoproteins (HDL3) to deliver cholesteryl esters to human granulosa cells and describes the selective cholesterol pathway by which this occurs. Luteinized cells obtained from subjects undergoing in vitro fertilization-embryo transfer procedures were incubated with native HDL3 (or radiolabeled or fluorescently labeled HDL cholesteryl esters) to determine whether cells from humans (in which HDL is not the primary circulating lipoprotein species) can nevertheless interiorize and appropriately process cholesteryl esters for steroidogenesis. The results indicate that hormone-stimulated granulosa cells actively and efficiently use human HDL-derived cholesterol for progesterone production. More than 95% of the mass of HDL cholesteryl esters entering cells does so through the nonlysosomal (selective) pathway, i.e. cholesteryl esters released from HDL are taken up directly by the cells without internalization of apoproteins. Once internalized, the cholesteryl esters are either hydrolyzed and directly used for steroidogenesis or stored in the cells as cholesteryl esters until needed. The utilization of the internalized cholesteryl esters is a hormone-regulated event; i.e. luteinized human granulosa cells internalize and store large quantities of HDL-donated cholesteryl esters when available, but further processing of the cholesteryl esters (hydrolysis, re-esterification, or use in steroidogenesis) does not occur unless the cells are further stimulated to increase progesterone secretion. |
| Human HDL cholesterol levels are determined by apoA-I fractional catabolic rate, which correlates inversely with estimates of HDL particle size. Effects of gender, hepatic and lipoprotein lipases, triglyceride and insulin levels, and body fat distribution Brinton, E. A., S. Eisenberg, et al. (1994), Arterioscler Thromb 14(5): 707-20. Abstract: High-density lipoprotein (HDL) cholesterol (HDL-C) levels are a strong inverse predictor of atherosclerosis risk, but the physiological determinants of HDL-C levels are poorly understood. We selected 57 human subjects (30 women and 27 men) with a broad range of HDL-C levels and performed turnover studies of apolipoprotein (apo)A-I and apoA-II, the two major apolipoproteins of HDL, to measure the fractional catabolic rate (FCR) and production or transport rate (TR) of these proteins. We also measured several other parameters known to correlate with HDL-C levels to test for their interrelations and to postulate mechanisms of regulation of HDL-C levels. As expected, the women had higher levels of HDL-C (56.7 +/- 21.4 versus 45.1 +/- 16.3 mg/dL, mean +/- SD; P =.03) and apoA-I (147 +/- 32 versus 126 +/- 29 mg/dL, P =.01) than men and did not differ in apoA-II levels (34.5 +/- 7.4 versus 33.3 +/- 7.5 mg/dL, P >.2). The FCR of apoA-I tended to be lower in the women (0.248 +/- 0.077 versus 0.277 +/- 0.069 pools/d, P =.1), although the difference was not statistically significant. The FCR of apoA-II was also lower (0.184 +/- 0.043 versus 0.216 +/- 0.056 pools/d, P =.02). In contrast, the apoA-I TR was equal in women and men (12.0 +/- 1.6 versus 12.1 +/- 2.8 mg/kg per day, P >.2), and there was a trend toward lower apoA-II TR in women (2.19 +/-.62 versus 2.61 +/- 1.06 mg/kg per day, P =.07). Linear regression analysis revealed a strong inverse correlation between HDL-C levels and the FCRs of apoA-I and apoA-II (r = -.81 and -.76, respectively; P <.0001 for both). In contrast, there was little or no association between HDL-C and the TRs of apoA-I and apoA-II (r =.06 and -.35, P = not significant and.01, respectively). In stepwise multiple linear regression analysis, apoA-I FCR alone accounted for 66% of the variability in HDL-C; two other variables accounted for an additional 7%. Due to the importance of apoA-I FCR, its determinants were sought among the remaining variables.(ABSTRACT TRUNCATED AT 400 WORDS) |
| Human hepatic triglyceride lipase expression reduces high density lipoprotein and aortic cholesterol in cholesterol-fed transgenic mice Busch, S. J., R. L. Barnhart, et al. (1994), J Biol Chem 269(23): 16376-82. Abstract: We have produced a line of transgenic mice expressing human hepatic triglyceride lipase (hH-TGL) to examine the in vivo effects of hepatic lipase expression on high density lipoprotein catabolism. Activation of metallothionine I promoter-hH-TGL cDNA transgene produced high levels of lipase mRNA in liver, heart, and kidney and elevated enzyme activity as assayed in post-heparin plasma. In a series of hyperlipidemic diet studies in which zinc was included in the diet to induce the transgene, hH-TGL expression was associated with a 34% lowering of plasma HDL-cholesterol levels (p < 0.01) when compared with animals on the same hyperlipidemic diet without zinc. This lowering of HDL cholesterol was paralleled by a decrease in total cholesterol and a decrease in HDL particle size. SDS-polyacrylamide gel electrophoresis analysis of the smaller HDL particles revealed that apolipoprotein AI was still the major apoprotein associated with the HDL. Quantitative analysis of abdominal aortic cholesterol content from the same animals suggests that the observed changes in plasma HDL by hH-TGL over-expression correlated with a decrease in the accumulation of aortic cholesterol (42%, p < 0.01). These data support the hypothesis that hH-TGL mediates a non-receptor pathway for the clearance of cholesterol from the plasma compartment. |
| Human lens cholesterol concentrations in patients who used lovastatin or simvastatin Mitchell, J. and R. J. Cenedella (1999), Arch Ophthalmol 117(5): 653-7. Abstract: OBJECTIVE: To determine whether long-term therapeutic use of the hypocholesterolemic drugs lovastatin and simvastatin significantly alters the distribution and concentration of cholesterol in the human lens. Such changes might precede observable alterations in lens structure. METHODS: Pairs of lenses (9-13 pairs) from patients (age range, 46-81 years) who had been taking lovastatin or simvastatin before their death (estimated for the previous 2-4 years) and lenses from similarly aged control subjects were divided into outer cortex and inner cortex plus nucleus by dissolution in a detergent-containing buffer. Ten minutes of dissolution removed 17% to 19% of the lens total volume, which accounted for about 20% of the width of the equatorial cortex and 75% of the width of the sagittal cortex. This fraction plus the residual lens was homogenized, saponified, and assayed for cholesterol by gas-liquid chromatography. RESULTS: The cortex of adult control lenses contained about 4 microg of cholesterol per cubic millimeter of volume. This concentration increased to 10 to 15 microg/mm3 in the adult nucleus and decreased to about 6 microg/mm3 in the juvenile and fetal nucleus. Treatment with neither lovastatin nor simvastatin significantly altered the concentration of cholesterol in either the cortex or nuclear fractions. CONCLUSIONS: Variations in concentration of cholesterol along the radii of the lens reflect differences in the density or packing of fiber cell membranes. The observed distribution of cholesterol supports the recent model of the adult lens structure, which, from surface to center, is the cortex, adult nucleus,juvenile nucleus, fetal nucleus, and embryonic nucleus. Finding no significant changes in concentration of cholesterol in the cortex formed during treatment with lovastatin or simvastatin reinforces the results of clinical studies that indicate a high lenticular safety of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Nevertheless, caution is encouraged in assuming a similar ocular safety in newer drugs that inhibit cholesterol synthesis at later metabolic steps. CLINICAL RELEVANCE: Does clinical use of hypocholesterolemic drugs alter lens cholesterol? |
| Human leukemia inhibitory factor upregulates LDL receptors on liver cells and decreases serum cholesterol in the cholesterol-fed rabbit Moran, C. S., J. H. Campbell, et al. (1997), Arterioscler Thromb Vasc Biol 17(7): 1267-73. Abstract: In a previous study, we found that the cytokine (human) leukemia inhibitory factor (hLIF) significantly reduced plasma cholesterol levels and the accumulation of lipid in aortic tissues of cholesterol-fed rabbits after 4 weeks of treatment. The mechanisms by which this occurs were investigated in the present study. This involved examining the effect of hLIF on (1) the level of plasma cholesterol at different times throughout the 4-week treatment and diet period; (2) smooth muscle cell (SMC) and macrophage-derived foam cell formation in vitro; and (3) LDL receptor expression and uptake in the human hepatoma cell line HepG2. At time zero, an osmotic minipump (2-mL capacity; infusion rate, 2.5 microL/h; 28 days) containing either hLIF (30 micrograms kg-1.d-1) or saline was inserted into the peritoneal cavity of New Zealand White rabbits (N = 24). Rabbits were divided into four groups of six animals each. Group 1 received a normal diet/saline; group 2, a normal diet/hLIF; group 3, a 1% cholesterol diet/saline; and group 4, a 1% cholesterol diet/hLIF. hLIF had no effect on the plasma lipids or artery wall of group 2 rabbits (normal diet). However, in group 4 rabbits, plasma cholesterol levels and the percent surface area of thoracic aorta covered by fatty streaks was decreased by approximately 30% and 80%, respectively, throughout all stages of the 4-week treatment period. In vitro, hLIF failed to prevent lipoprotein uptake by either SMCs or macrophages (foam cell formation) when the cells were exposed to beta-VLDL for 24 hours. In contrast, hLIF (100 ng/mL) added to cultured human hepatoma HepG2 cells induced a twofold or threefold increase in intracellular lipid accumulation in the medium containing 10% lipoprotein-deficient serum or 10% fetal calf serum, respectively. This was accompanied by a significant non-dose-dependent increase in LDL receptor expression in hLIF-treated HepG2 cells incubated with LDL (20 micrograms/mL) when compared with controls (P <.05) incubated in control medium alone (P <.05). We suggest that the hLIF-induced lowering of plasma cholesterol and tissue cholesterol levels (inhibition of fatty streak formation) in the hyperlipidemic rabbit is due in part to upregulation of hepatic LDL receptors, with resultant increased clearance of lipoprotein-associated cholesterol from the circulation. There is an additional and as-yet-unknown mechanism acting at the level of the vessel wall that appears to be affecting the process of arterial cholesterol accumulation. |
| Human liposarcoma cell line, SW872, secretes cholesteryl ester transfer protein in response to cholesterol Richardson, M. A., D. T. Berg, et al. (1996), J Lipid Res 37(5): 1162-6. Abstract: Cholesteryl ester transfer protein (CETP) mediates the exchange of phospholipids and neutral lipids between the plasma lipoproteins, and plays an important role in high density lipoprotein (HDL) metabolism. While there are reports of low-level CETP secretion from cultured cells, the lack of a good model cell line has hampered the detailed study of CETP regulation and secretion. In this study, we have found that the human liposarcoma cell line, SW872, secretes cholesteryl ester transfer protein at levels substantially higher than observed from other cell lines. The secretion of CETP from this adipose-derived cell was up-regulated by 25-OH cholesterol and by low density lipoprotein (LDL) cholesterol in a concentration-dependent manner. Analysis of both full length and exon 9-deleted CETP mRNA demonstrated increases in response to LDL and 25-OH cholesterol, providing evidence for regulation at the message level. Our results suggest that the CETP-producing SW872 cell line may provide a model in which to study the regulation of this important modulator of lipoprotein metabolism. |
| Human low-density lipoproteins: oxidative modification and its relation to age, gender, menopausal status and cholesterol concentrations Mosinger, B. J. (1997), Eur J Clin Chem Clin Biochem 35(3): 207-14. Abstract: Recently much evidence has accumulated indicating that oxidative modification of atherogenic lipoproteins plays an important role in atherogenesis. The goal of this study was to ascertain whether any association exists between this and the previously incriminated risk factors of atherosclerotic cardiovascular disease like age, gender and cholesterol concentration. Serum lipid profile, low-density lipoprotein (LDL) composition and indicators of LDL oxidation were examined in a cohort of healthy, predominantly middle aged men and women. LDL oxidation was assessed using the copper catalysis method, and monitored routinely by the increase in conjugated dienes over 4 to 24 hours. A more objective computer-aided technique was used to estimate the oxidative indices based on the sigmoidal fit to data. No marked differences between men and women were found with respect to mean age, total and LDL cholesterol, LDL protein and oxidation of LDL. The post-menopausal as compared to pre-menopausal status was associated with a greater extent of LDL oxidation, as well as with higher total serum cholesterol and its fractions, LDL cholesterol and LDL protein. No such differences were found in the data for men appropriately separated according to age. In a group with high risk LDL cholesterol, the total LDL oxidation was higher, as well as age and total cholesterol. Lag time and half-time of LDL oxidation were significantly shorter, while the oxidation rate of LDL was significantly faster when compared with data in the lower quartile. About six percent of participants had a considerably prolonged initial oxidation phase. These persons also showed low total and LDL cholesterol. High oxidation resistance was reversible and most probably caused by very low pre-existent oxidation products. Multiple regression analysis showed that the closest association among age, gender, lipid profiles and LDL oxidation indices existed between LDL cholesterol and conjugated diene production in both sexes (men: r = 0.93; women: r = 0.81). This association remained high even if adjusted for age. As in earlier epidemiological studies using logistic regression and showing age- and gender-related rising frequency of coronary heart disease, the present paper demonstrated age- and gender-related rising frequency of highly oxidized LDL. In both cases it was closely associated with an increasing LDL cholesterol concentration. |
| Human malformation syndromes due to inborn errors of cholesterol synthesis Porter, F. D. (2003), Curr Opin Pediatr 15(6): 607-13. Abstract: PURPOSE OF REVIEW: This review covers a group of human malformation syndromes, which are caused by inborn errors of cholesterol synthesis. The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation, and mental retardation syndrome that is the prototypical example of this group of disorders. In the 10 years since the biochemical cause of SLOS was identified, other malformation syndromes have been shown to result from defects in this pathway. These include desmosterolosis, lathosterolosis, X-linked dominant chondrodysplasia punctata type 2 (CDPX2), congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM dysplasia), and some cases of Antley-Bixler syndrome. These disorders represent the first true merging of dysmorphology with biochemical genetics. RECENT FINDINGS: Recent studies report the identification of human lathosterolosis patients, indicate that SLOS is a relatively common genetic disorder that may be a major unrecognized cause of fetal loss, suggest that correction of the biochemical defect can improve central nervous system function, and show that perturbed sonic hedgehog signaling due to decreased sterol levels likely underlies some of the malformations in SLOS and lathosterolosis. SUMMARY: Recognition of the biochemical defect in these syndromes has given insight into the role that cholesterol plays during normal development, into understanding the pathophysiological processes that underlie the clinical problems found in these disorders, and into developing therapeutic interventions. |
| Human milk total lipid and cholesterol are dependent on interval of sampling during 24 hours Jensen, R. G., C. J. Lammi-Keefe, et al. (1995), J Pediatr Gastroenterol Nutr 20(1): 91-4. |