Cholesterol Journal Articles

Record 13221 to 13240

Triglyceride-rich lipoprotein cholesterol exceeds low-density lipoprotein cholesterol in hypertriglyceridemia patients
Ai, M., A. Tanaka, et al. (2001), Horm Metab Res 33(10): 612-7.
Abstract: The atherogenicity of triglyceride-rich lipoprotein has been revealed. This study was performed to explore the clinical importance of triglyceride-rich lipoprotein by measuring its cholesterol content and comparing it with other lipoprotein fractions. Blood samples were obtained from 103 patients whose fasting plasma triglyceride concentration exceeded 300 mg/dl. The cholesterol monitor using the technique of high-performance liquid chromatography was used for the measurement of their plasma cholesterol concentrations and the determination of cholesterol distribution among lipoprotein fractions. This monitor showed 4 peaks: large-triglyceride-rich lipoprotein, small-triglyceride-rich lipoprotein, low-density lipoprotein, and high-density lipoprotein. Total cholesterol increased with increasing triglyceride. The increment of total cholesterol was nearly equal to that of small-triglyceride-rich lipoprotein cholesterol. Small-triglyceride-rich lipoprotein cholesterol exceeded low-density lipoprotein cholesterol where plasma triglyceride concentration was over 500 mg/dl. In conclusion, triglyceride-rich lipoprotein may be clinically important for hypertriglyceridemic patients as a source of cholesteryl ester in arteriosclerotic plaques, and increased triglyceride-rich lipoprotein cholesterol may be used as a basis for hypertriglyceridemia atherogenicity. Our study suggests that hypertriglyceridemia should be treated to prevent arteriosclerotic disease.

Triglyceride-rich lipoproteins inhibit cholesterol efflux to apolipoprotein (apo) A1 from human macrophage foam cells
Palmer, A. M., N. Murphy, et al. (2004), Atherosclerosis 173(1): 27-38.
Abstract: High circulating levels of triglyceride-rich lipoproteins (TGRL) represent an independent risk factor for coronary artery disease. Here, we show that TGRL inhibit the efflux of cholesterol from 'foam cell' macrophages to lipid-poor apolipoprotein (apo) A1, and may thereby inhibit arterial reverse cholesterol transport and promote the formation of atherosclerotic lesions. Human (THP-1) monocyte-derived macrophages were pre-incubated (48 h) with acetylated low-density lipoprotein (AcLDL) to provide a foam cell model of cholesterol efflux to apoA1. Pre-incubation of macrophage 'foam cells' with TGRL (0-200 microg/ml, 0-24 h) inhibited the efflux of exogenously radiolabelled (3H), endogenously synthesised (14C) and cellular cholesterol mass to lipid-poor apoA1, but not control medium, during a (subsequent) efflux period. This inhibition is dependent upon the length of prior exposure to, and concentration of, TGRL employed, but is independent of changes in intracellular triglyceride accumulation or turnover of the cholesteryl ester pool. Despite the negative impact of TGRL on cholesterol efflux, major proteins involved in this process--namely apoE, ABCA1, SR-B1 and caveolin-1--were unaffected by TGRL pre-incubation, suggesting that exposure to these lipoproteins inhibits an alternate, and possibly novel, anti-atherogenic pathway.

Triglyceride-rich lipoproteins of subjects heterozygous for apolipoprotein E2(Lys146-->Gln) are inefficiently converted to cholesterol-rich lipoproteins
Mulder, M., H. van der Boom, et al. (1994), Atherosclerosis 108(2): 183-92.
Abstract: The APOE*2(Lys146-->Gln) allele behaves like a dominant trait in the expression of familial dysbetalipoproteinemia (FD) (Smit et al., J. Lipid Res. 1990; 31: 45-53). FD patients carrying the APOE*2(Lys146-->Gln) allele exhibit less elevated cholesterol to triglyceride ratios in the d < 1.019 g/ml lipoprotein density fraction as compared to classical FD patients displaying homozygosity for the APOE*2(Arg158-->Cys) allele (0.8 vs. 1.4). Upon treatment of complete serum with lipoprotein lipase (LPL), the mean cholesterol to triglyceride molar ratio of the d < 1.019 g/ml lipoprotein fraction in these FD patients increased only marginally (from 0.8 to 1.1), as compared with that of classical FD subjects (from 1.4 to 2.6) and non-FD control subjects (from 0.7 to 1.5). In order to obtain further evidence for an inefficient lipolysis of the d < 1.019 g/ml lipoprotein fraction in APOE*2(Lys146-->Gln) carriers, possibly in combination with a less efficient cholesteryl ester transfer protein (CETP) activity, blood samples of APOE*2(Lys146-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys149-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys146-->Gln) FD patients, the increase in plasma cholesterol was mainly confined to the very low density lipoprotein (VLDL) fraction, whereas in classical FD patients, the levels of cholesterol in the intermediate density lipoprotein (IDL) fraction was also dramatically increased (ratios of VLDL to IDL cholesterol are 4.7 and 2.6, respectively). Family analyses of the APOE*2(Lys146-->Gln) FD subjects showed that the apo E to apo B ratio in the d < 1.019 g/ml lipoprotein fraction of allele carriers is 3.5 times as high as that found in non-carriers (2.8 vs. 0.8, by wt.). Also, in the APOE*2(Lys146-->Gln) allele carrying family members, the ratio of cholesterol to triglyceride of the d < 1.019 g/ml lipoprotein fraction is less markedly elevated upon addition of LPL when compared to that in non-carrying controls (from 1.1 to 1.8 vs 0.7 to 1.6). The efficiency of the d < 1.019 g/ml lipoprotein fraction of APOE*2(Lys146-->Gln) FD patients to compete with low density lipoprotein (LDL) for binding to the LDL receptor is intermediate to that of controls and classical APOE*2(Arg158-->Cys) homozygous FD patients. These findings suggest that in APOE*2(Lys146-->Gln) allele carriers, the conversion of VLDL into IDL is impaired due to an inefficient lipolysis, possibly in combination with a retarded CETP activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Triglycerides and HDL-cholesterol as risk factors for ischemic heart disease. Results from the Quebec cardiovascular study
Lamarche, B., J. P. Despres, et al. (1996), Atherosclerosis 119(2): 235-45.
Abstract: The relative importance of reduced plasma high density lipoprotein-cholesterol (HDL-C) levels and elevated plasma triglyceride (TG) concentrations as risk factors for ischemic heart disease (IHD) was examined in a sample of 2177 men from the Quebec City suburbs. The sample included 202 men with known IHD. The relationship between HDL-C and TG levels, although significant (r = -0.49, P < 0.0001), was not linear, as most of the variation in HDL-C levels was observed within TG levels below 2.5 mmol/l. Reduced HDL-C (< 0.9 mmol/l) was a prevalent condition in men with IHD (50%) compared to those without IHD (30%). On the other hand 26% and 20% of men with and without IHD, respectively, had elevated TG levels (TG > 2.3 mmol/l). A 2-fold increase in prevalence odds ratio (OR) was observed in men with TG levels > 2.3 mmol/l (95% confidence intervals (CI) 1.2;3.3). No residual association between elevated TG levels and IHD was found, however, after adjustment for HDL-C concentrations (OR 1.2, 95% CI 0.7;2.1). On the other hand, HDL-C remained a significant predictor of IHD after adjustment for other risk factors (OR 0.3, 95%, CI 0.2;0.6). Men with reduced HDL-C levels were also characterized by a cluster of risk factors such as obesity, diabetes mellitus and hypertension, which may contribute to increase the risk of IHD. Finally, the independent interpretation of cholesterol, TG or LDL-C levels may lead to an inadequate prediction of risk, as a large number of IHD patients showed a cluster of risk factors which included low HDL-C concentrations.

Triglycerides and serum cholesterol
Castelli, W. P. (1991), Postgrad Med 90(8): 47, 50, 53.

Triglycerides are major determinants of cholesterol esterification/transfer and HDL remodeling in human plasma
Murakami, T., S. Michelagnoli, et al. (1995), Arterioscler Thromb Vasc Biol 15(11): 1819-28.
Abstract: Lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) are responsible for the esterification of cell-derived cholesterol and for the transfer of newly synthesized cholesteryl esters (CE) from HDL to apoB-containing lipoproteins in human plasma. LCAT and CETP are also crucial factors in HDL remodeling, a process by which HDL particles with a high capacity for cell cholesterol uptake are generated in plasma. In the present study, cholesterol esterification and transfer were evaluated in 60 patients with isolated hypercholesterolemia (HC, n = 20) and isolated (HTG, n = 20) or mixed hypertriglyceridemia (MHTG, n = 20) and in 20 normolipidemic healthy individuals (NL). Cholesterol esterification rate (CER) and net CE transfer rate (CETR) were measured in whole plasma. LCAT and CETP concentrations were determined by specific immunoassays. HDL remodeling was analyzed by monitoring changes in HDL particle size distribution during incubation of whole plasma at 37 degrees C. Mean CER and CETR were 48% and 73% higher, respectively, in hypertriglyceridemic (HTG + MHTG) versus normotriglyceridemic individuals. HDL remodeling was also significantly accelerated in plasma from hypertriglyceridemic patients. Strong positive correlations were found in the total sample between plasma and VLDL triglyceride levels and CER (r =.722 and r =.642, respectively), CETR (r =.510 and r =.491, respectively), and HDL remodeling (r =.625 and r =.620, respectively). No differences in plasma LCAT and CETP concentrations were found among the various groups except for a tendency toward higher CETP levels in hypercholesterolemic patients (+51% in MHTG and +20% in HC) versus control subjects (NL). By stepwise regression analysis, VLDL triglyceride level was the sole significant predictor of CER and CETR and contributed significantly together with baseline HDL particle distribution to HDL remodeling. These results indicate that plasma triglyceride level is a major factor in the regulation of cholesterol esterification/transfer and HDL remodeling in human plasma, whereas LCAT/CETP concentrations play a minor role in the modulation of reverse cholesterol transport.

Triglyceride-to-HDL cholesterol ratio in the dyslipidemic classification of type 2 diabetes
Wagner, A. M., A. Perez, et al. (2005), Diabetes Care 28(7): 1798-800.

Triiodothyronine exerts a major pleiotropic effect on reverse cholesterol transport phenotypes
Comuzzie, A. G., J. Blangero, et al. (1996), Arterioscler Thromb Vasc Biol 16(2): 289-93.
Abstract: The thyroid hormone triiodothyronine (T3) is known to be a potent mediator of APOA1 gene expression. With the use of multivariate quantitative genetic analysis, we have assessed the magnitude of shared effects of T3 on plasma concentrations of apolipoprotein AI (apo AI) and three related phenotypes: HDL-C, apo AII, and LpAI (which is a concentration of apo AI that contains HDL particles). Maximum likelihood techniques were used to simultaneously estimate mean effects and variance components in large, extended Mexican American families living in San Antonio, Tex. We found that T3 accounted for 16%, 23%, 21%, and 37% of the additive genetic variance in HDL-C, apo AI, apo AII, and LpAI, respectively, while explaining virtually none of the random environmental variance in these phenotypes. T3 also has a pronounced effect on the pairwise genetic correlations among the four phenotypes: After the pleiotropic effects of T3 concentrations are controlled for, the genetic correlations are reduced by 6% in the case of HDL-C and apo AI and 97% for apo AII and LpAI. Thus, genes that influence T3 have a significant effect on HDL-C, apo AI, apo AII, and LpAI and also on the correlations among these phenotypes.

Triolein-phosphatidylcholine-cholesterol emulsions as substrates for lipoprotein and hepatic lipases
Clark, S. B. and H. L. Laboda (1991), Lipids 26(1): 68-73.
Abstract: Lipolysis of emulsified glycerol tri9,10-3Holeate by lipoprotein lipase purified from bovine milk (E.C.3.1.1.34) and by hepatic lipase purified from rat liver perfusate was studied as a function of the phosphatidylcholine molecular species and the cholesterol content of the emulsions. Overall, the activities of the two enzymes were similar on a molar basis. Lipoprotein lipase initial lipolysis rates also were comparable for emulsions made with egg phosphatidylcholine or with saturated (dimyristoyl, dipalmitoyl and distearoyl) phosphatidylcholines when cholesterol was low. Increasing the cholesterol content of the emulsion from 2-3 mole percent to 7-14 mole percent reduced triolein lipolysis by lipoprotein lipase in emulsions made with saturated phosphatidylcholines. Rat hepatic lipase was more sensitive to increased cholesterol in emulsions made with saturated phosphatidylcholines than was lipoprotein lipase. The ability to maintain triolein lipolysis during longer incubations differed strikingly among the emulsions and for the two enzymes. Lymph chylomicrons were better substrates for both enzymes than any of the emulsions.

Triple lipid screening test: a homogeneous sequential assay for HDL-cholesterol, total cholesterol, and triglycerides
Sampson, M. L., A. Aubry, et al. (2001), Clin Chem 47(3): 532-9.
Abstract: BACKGROUND: The analysis of lipids in serum lipoprotein fractions is useful in assessing the risk for coronary artery disease, but it typically involves performing multiple tests. An automated single-tube assay, referred to as the triple lipid screening (TLS) test, can be used for measuring HDL-cholesterol (HDL-C), total cholesterol, and triglycerides (TGs) with no specimen pretreatment. METHODS: The first part of the assay is based on a homogeneous assay for HDL-C that uses either an anti-apolipoprotein B antibody (TLS-A test) or a polyanion (TLS-B test) that blocks the enzymatic measurement of cholesterol on the non-HDL fraction. After the addition of deoxycholate, which solubilizes the unreacted cholesterol from the non-HDL fraction, the remaining cholesterol in the sample is subsequently measured enzymatically. Using the same enzyme detection system as the cholesterol assay, TGs are measured in the last step, after the addition of the enzymes for the TG assay. RESULTS: The TLS assay (y) had acceptable analytic performance and compared favorably with standard tests (x) for each analyte: for HDL-C, TLS-A = 0.99x + 0.19 (R = 0.980); TLS-B = 1.00x - 0.15 (R = 0.974); for total cholesterol, TLS-A = 1.03x + 0.12 (R = 0.997); TLS-B = 1.07x - 0.30 (R = 0.965); and for TGs, TLS-A = 1.02x + 0.02 (R = 0.988); TLS-B = 1.04x - 0.28 (R = 0.980). CONCLUSIONS: The TLS test is a single-tube homogeneous assay for the analysis of all of the major serum lipoprotein fractions and can be used as a simple screening test for the detection of hyperlipidemia.

Troglitazone directly increases HDL cholesterol levels
Nozue, T., I. Michishita, et al. (1999), Diabetes Care 22(2): 355-6.

Troglitazone, an antidiabetic agent, inhibits cholesterol biosynthesis through a mechanism independent of peroxisome proliferator-activated receptor-gamma
Wang, M., S. C. Wise, et al. (1999), Diabetes 48(2): 254-60.
Abstract: Troglitazone is an antidiabetic agent of the thiazolidinedione family. It is generally believed that thiazolidinediones exert their insulin-sensitizing activity through activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the steroid nuclear receptor superfamily. In the present study, we examined the effect of troglitazone on cholesterol biosynthesis in cultured Chinese hamster ovary (CHO) cells. Troglitazone inhibited biosynthesis of cholesterol, but not that of total sterols, in a dose-dependent manner, with a half-maximal concentration (IC50) value of 8 micromol/l. At 20 micromol/l, troglitazone inhibited cholesterol biosynthesis by more than 80%, resulting in the accumulation of lanosterol and several other sterol products. This inhibitory effect observed in CHO cells was also reproduced in HepG2, L6, and 3T3-L1 cells, suggesting that there is a common pathway for this troglitazone action. One hour after removal of troglitazone from the culture medium, disappearance of the accumulated sterols was accompanied by restored cholesterol synthesis, indicating that those accumulated sterols are precursors of cholesterol. PPAR-gamma reporter assays showed that PPAR-gamma activation by troglitazone was completely blocked by actinomycin D and cycloheximide. In contrast, the inhibition of cholesterol synthesis by troglitazone remained unchanged in the presence of the above compounds, suggesting that this inhibition is mechanistically distinct from the transcriptional regulation by PPAR-gamma. Like troglitazone, two other thiazolidinediones, ciglitazone and englitazone, exhibited similar inhibitory effect on cholesterol synthesis; however, other known PPAR-gamma ligands such as BRL49653, pioglitazone, and 15-deoxy-delta(12,14)-prostaglandin J2 showed only weak or no inhibition. The dissociation of PPAR-gamma binding ability from the potency for inhibition of cholesterol synthesis further supports the conclusion that inhibition of cholesterol biosynthesis by troglitazone is unlikely to be mediated by PPAR-gamma.

Trypsin-sensitive and lipid-containing sites of the macrophage extracellular matrix bind apolipoprotein A-I and participate in ABCA1-dependent cholesterol efflux
Burgess, J. W., R. S. Kiss, et al. (2002), J Biol Chem 277(35): 31318-26.
Abstract: A unique property of the extracellular matrix of J774 and THP-1 cells has been identified, which contributes to the ability of these cells to promote cholesterol efflux. We demonstrate high level apolipoprotein (apo) A-I binding to macrophage cells (THP-1 and J774) and to their extracellular matrix (ECM). However, high level apoA-I binding is not observed on fibroblasts, HepG2 cells, or U937 cells (a macrophage cell line that does not efflux cholesterol to apoA-I or bind apoA-I on their respective ECM). Binding to the ECM of THP-1 or J774 macrophages depends on the presence of apoA-I C-terminal helices and is markedly reduced with a mutant lacking residues 187-243 (apoA-I Delta(187-243)), suggesting that the hydrophobic C terminus forms a hydrophobic interaction with the ECM. ApoA-I binding is lost upon trypsin treatment or with Triton X-100, a preparation method that de-lipidates the ECM. However, binding is recovered with re-lipidation, and is preserved with ECM prepared using cytochalasin B, which conserves the endogenous phospholipid levels of the ECM. We also demonstrate that specific cholesterol efflux to apoA-I is much reduced in cells released from their native ECM, but fully restored when ECM-depleted cells are added back to ECM in the presence of apoA-I. The apoA-I-mediated efflux is deficient in plated or suspension U937 macrophages, but is restored to high levels when the suspension U937 cells are reconstituted with the ECM of J774 cells. The ECM-dependent activity was much reduced in the presence of glyburide, indicating participation of ABCA1 (ATP-binding cassette transporter 1) in the efflux mechanism. These studies establish a novel binding site for apoA-I on the macrophage ECM that may function together with ABCA1 in promoting cholesterol efflux.

TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study)
Meier, C., J. J. Staub, et al. (2001), J Clin Endocrinol Metab 86(10): 4860-6.
Abstract: This study evaluated the effect of physiological, TSH-guided, L-thyroxine treatment on serum lipids and clinical symptoms in patients with subclinical hypothyroidism. Sixty-six women with proven subclinical hypothyroidism (TSH, 11.7 +/- 0.8 mIU/liter) were randomly assigned to receive L-thyroxine or placebo for 48 wk. Individual L-thyroxine replacement (mean dose, 85.5 +/- 4.3 microg/d) was performed based on blinded TSH monitoring, resulting in euthyroid TSH levels (3.1 +/- 0.3 mIU/liter). Lipid concentrations and clinical scores were measured before and after treatment. Sixty-three of 66 patients completed the study. In the L-thyroxine group (n = 31) total cholesterol and low density lipoprotein cholesterol were significantly reduced -0.24 mmol/liter, 3.8% (P = 0.015) and -0.33 mmol/liter, 8.2% (P = 0.004), respectively. Low density lipoprotein cholesterol decrease was more pronounced in patients with TSH levels greater than 12 mIU/liter or elevated low density lipoprotein cholesterol levels at baseline. A significant decrease in apolipoprotein B-100 concentrations was observed (P = 0.037), whereas high density lipoprotein cholesterol, triglycerides, apolipoprotein AI, and lipoprotein(a) levels remained unchanged. Two clinical scores assessing symptoms and signs of hypothyroidism (Billewicz and Zulewski scores) improved significantly (P = 0.02). This is the first double blind study to show that physiological L-thyroxine replacement in patients with subclinical hypothyroidism has a beneficial effect on low density lipoprotein cholesterol levels and clinical symptoms of hypothyroidism. An important risk reduction of cardiovascular mortality of 9-31% can be estimated from the observed improvement in low density lipoprotein cholesterol.

Tumor diseases of the blood system: age, cholesterol level and erythrocyte count
Genkin, A. A. (1998), Ter Arkh 70(3): 60-6.
Abstract: AIM: Illustration of potentialities of computer technologies in processing data from case histories MATERIALS AND METHODS: Routine clinical and laboratory data on 263 hemoblastosis patients were processed with the use of the exploring system. RESULTS: A paradoxical negative relationship was discovered between blood cholesterol and age (R = -0.345, p < 0.00001), and a positive correlation between cholesterol and number of red cells (R = 0.379, p < 0.00001). In comparison of groups with low and high cholesterol, the latter group showed more favourable values of hemoglobin, red cells, other hematological and biochemical parameters. It seems that among hemoblastosis patients and healthy subjects there are subjects with standard age-related changes of cholesterol and paradoxical changes (a negative correlation). The conception about high level of cholesterol as a factor stimulating proliferation of normal and affected cells in patients with hemoblastoses appears doubtful. At least it is not correct to connect a combination hypocholesterolemia + anemia with low pool of dividing cells. On the contrary, hypocholesterolemia in hemoblastoses indicates active tumor process with consequent anemia. CONCLUSION: Investigation of paradoxical relationships between age, cholesterol and red cell count (hemoglobin) will help understand general mechanisms of regulation of hemo- and immunogenesis in blood malignancies.

Tumor efficacy and biodistribution of linear polyethylenimine-cholesterol/DNA complexes
Furgeson, D. Y., J. W. Yockman, et al. (2004), Mol Ther 9(6): 837-45.
Abstract: Non-viral polymer/pDNA complexes were formed using linear polyethylenimine (LPEI) Mw 25 k conjugated to cholesterol in a T-shaped geometry (LPC-T) and pDNA encoding murine interleukin-12 (pmIL-12e). These complexes were subsequently injected weekly into BALB/c mice intravenously and locally for the treatment of murine renal cell adenocarcinoma (Renca) induced pulmonary metastases and subcutaneous (SC) Renca tumors, respectively. At the cessation of the pulmonary metastases study, the number of pulmonary metastases was significantly less (p < 0.001) with systemic injections of LPC-T/pmIL-12e formulations than with pmIL-12e alone or pmIL-12e complexed with LPEI, branched polyethylenimine (BPEI) Mw 25 k, or an LPEI/pEGFP control. In addition, biodistribution studies showed increased pulmonary levels of both the LPC-T carrier and pmIL-12e vector up to 3 hr after systemic injection of the LPC-T/pmIL-12e complexes into mice carrying pulmonary metastases. Furthermore, mice systemically treated with LPC-T/pmIL-12e showed a near linear profile in weight gain in the course of the pulmonary metastases study that suggests increased biocompatibility. Finally, due to favorable characteristics in vitro, LPC-T was also used for local (peritumoral) injection of SC Renca tumors. Tumor stasis and slight tumor regression were seen only with the LPC-T/pmIL-12e treated mice compared to BPEI/pmIL-12e, LPEI/pmIL-12e, and naked pmIL-12e controls. Thus, it was concluded that LPC-T is an effective carrier for passive targeting of the pulmonary tissue, treatment of Renca-induced pulmonary metastases, and local administration of Renca cell SC tumors.

Tumor necrosis factor mediates the effects of endotoxin on cholesterol and triglyceride metabolism in mice
Memon, R. A., C. Grunfeld, et al. (1993), Endocrinology 132(5): 2246-53.
Abstract: The host response to infection is frequently accompanied by changes in cholesterol and triglyceride (TG) metabolism. To determine the role of cytokines in mediating these changes, we studied the effects of endotoxin (LPS), tumor necrosis factor-alpha (TNF) and interleukin-1 beta (IL-1) on cholesterol and TG metabolism in C57Bl/6 (LPS-sensitive) mice and in C3H/HeJ (LPS-resistant) mice whose macrophages do not produce TNF and IL-1 in response to LPS. Sixteen hours after administration, LPS (1 micrograms/mouse) produced a 41% increase in serum cholesterol and a 62% increase in serum TG levels in C57Bl/6 mice whereas a 100-fold higher dose of LPS did not have a significant effect in C3H/HeJ mice. LPS (1 microgram/mouse) also produced a 8.6-fold increase in hepatic cholesterol synthesis and a 2.7-fold increase in hepatic fatty acid synthesis in C57Bl/6 mice but had no effect in C3H/HeJ mice. This suggests that macrophage produced cytokines such as TNF and IL-1 may be involved in mediating these effects of LPS. Additionally, LPS also increased the activity of hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. As seen with LPS, TNF and IL-1 also increased serum cholesterol and TG levels in C57Bl/6 mice. Moreover, TNF and IL-1 produced a 2.3- and 2.1-fold increase in hepatic HMG-CoA reductase activity, respectively. Finally, pretreatment of mice with anti-TNF antibodies, but not with an IL-1 receptor antagonist, blocked the effect of LPS on serum cholesterol and TG levels, hepatic cholesterol and fatty acid synthesis, and hepatic HMG-CoA reductase activity. These results suggest that whereas both TNF and IL-1 mimic the effects of LPS on cholesterol and TG metabolism, TNF may be the in vivo mediator of these late effects of LPS in mice.

Tumor radiosensitization based on the use of inhibitors of the mevalonate pathway of cholesterol synthesis
Miller, A. C. and D. Samid (1997), Adv Exp Med Biol 400B: 825-30.

Tumours of the central nervous system and concentration of total serum cholesterol and beta-lipoprotein in men and women
Gatchev, O., L. Rastam, et al. (1994), Br J Cancer 70(4): 668-71.
Abstract: Previous cross-sectional data suggest a positive association between serum cholesterol and brain neoplasms, but the results of cohort studies are inconclusive. There is evidence that in women the growth of meningiomas and astrocytomas depends on the hormonal status. The present investigation comprised data on serum cholesterol and beta-lipoprotein concentration among 229 participants in a health survey with subsequently diagnosed central nervous system (CNS) tumours. Data analyses included comparison of mean serum cholesterol and beta-lipoprotein level between cases and randomly selected controls--five for each case, matched for sex, age at screening and time of examination. The results showed a positive relation between the beta-lipoprotein level and the development of a CNS tumour (benign or malignant) in women under 50 years of age, and a negative association in those of older age with development of malignant tumours, which implies a possible influence of the menopausal status. Repeating the computations after excluding cases diagnosed within 5 years from screening revealed significant associations also between the serum cholesterol concentration and the development of a malignant CNS tumour, with a pattern similar to that of beta-lipoprotein. In conclusion, in women, irregular variation in the beta-lipoprotein level, which is involved in the synthesis of progesterone in the CNS, may enhance oncogenic transformation of astrocytes and meningeal cells; however, transformation of the latter is restricted to younger women.

Turnover of cholesterol and dipalmitoyl phosphatidylcholine in surfactant of adult rat lung
Jones, M. E., H. A. Barr, et al. (1993), Lipids 28(3): 173-9.
Abstract: In order to compare the turnover of two major surfactant components, 1 alpha,2 alpha (n)-3Hcholesterol and methyl14C choline dipalmitoyl phosphatidylcholine (DPPC) were introduced as lamellar bodies via the trachea into lightly anesthetized rats which were then allowed to recover. The radiotracers were assumed to have entered the alveolar surfactant pool and to have subsequently recycled in part into the lamellar bodies of alveolar type II cells. For DPPC, the specific activity vs. time curves of tubular myelin rich (alv-1) and tubular myelin poor (alv-2) alveolar lavage fractions were similar, and there was a plausible precursor-product relationship between lamellar bodies and either (or both) of these compartments. In contrast, however, the specific activities of alv-1 and alv-2 for cholesterol were quite different, allowing us to reject the hypothesis of a precursor-product relationship between classical lamellar bodies and alv-2. The estimated turnover time for DPPC in alv-1 was 240 or 206 min, depending on which subfraction of lamellar bodies one takes to be the precursor. For cholesterol it was 583 or 624 min. These longer turnover times for cholesterol should lead to a greater than twofold increase in the relative concentration of cholesterol in the putative product compartment. Such an increase was not found. We interpret this as reflecting either noncompartmental behavior of the alveolar surfactant pool, or multiple pools of lamellar bodies with different turnover times.(ABSTRACT TRUNCATED AT 250 WORDS)

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