| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Increased prevalence of aortic fatty streaks in cholesterol-fed rabbits administered intravenous cocaine: the role of vascular endothelium Kolodgie, F. D., P. S. Wilson, et al. (1993), Toxicol Pathol 21(5): 425-35. Abstract: Several recent postmortem studies suggest an increased prevalence of atherosclerosis in young habitual cocaine abusers. However, little is known about the effects of cocaine abuse on the vascular endothelium and its relationship to atherosclerosis. Therefore, the consequence of chronic administration of intravenous cocaine on the induction of aortic sudanophilia was examined. Male New Zealand White rabbits were fed a 0.5% cholesterol diet for 10 wk. During this period, animals were randomized to receive either cocaine-hydrochloride (0.25 mg/kg) intravenously (n = 17) twice daily; or an equivalent volume of 0.9% physiologic saline, control group (n = 16). Mean values for total circulating leukocytes and platelets and total plasma cholesterol and triglycerides were similar in both groups throughout the protocol. At the completion of the study, aortic sudanophilia was measured and expressed as a percentage of regional involvement (R1 = proximal 4 cm, R2 = middle 6 cm, and R3 = distal 10 cm). Statistical significance among groups was achieved in the proximal thoracic aorta (p = 0.057). No significant differences in sudanophilia were noted in the middle and distal segments. When animals were placed in subgroups according to percent total plaque involvement, there was a significant increased distribution of rabbits with a greater extent of sudanophilia in the cocaine-treated group as compared with control (p = 0.01, chi-square analysis). Immunocytochemical studies using the macrophage-specific and muscle actin-specific monoclonal antibodies demonstrated that sudanophilic areas in both groups were predominantly composed of macrophage-derived foam cells. Evaluation of plaque morphology showed an increase in intimal plaque thickness and in the number of macrophages and smooth muscle cells in cocaine-treated animals; however, group differences were not statistically significant. Because no significant differences were found in the cellular composition of atherosclerotic plaques between groups, further studies were performed to assess the effects of cocaine on the permeability function of cultured endothelial cell monolayers as a possible mechanism of increased sudanophilia. Cocaine (100 microM)-treated endothelial cell monolayers demonstrated an increased permeability to horseradish peroxidase during all time intervals studied (0-6 hr). Permeability differences were statistically significant at 30 min and 1 hr (p = 0.003 and 0.02, respectively). Collectively, these observations suggest that administration of cocaine to cholesterol-fed rabbits increases the prevalence of aortic sudanophilia via at least one possible mechanism involving enhanced vascular permeability. |
| Increased production of apolipoprotein B-containing lipoproteins in the absence of hyperlipidemia in transgenic mice expressing cholesterol 7alpha-hydroxylase Miyake, J. H., X. D. Doung, et al. (2001), J Biol Chem 276(26): 23304-11. Abstract: The finding that expression of a cholesterol 7alpha-hydroxylase (CYP7A1) transgene in cultured rat hepatoma cells caused a coordinate increase in lipogenesis and secretion of apoB-containing lipoproteins led to the hypothesis that hepatic production of apoB-containing lipoproteins may be linked to the expression of CYP7A1 (Wang, S.-L., Du, E., Martin, T. D., and Davis, R. A. (1997) J. Biol. Chem. 272, 19351-19358). To examine this hypothesis in vivo, a transgene encoding CYP7A1 driven by the constitutive liver-specific enhancer of the human apoE gene was expressed in C56BL/6 mice. The expression of CYP7A1 mRNA (20-fold), protein (approximately 10-fold), and enzyme activity (5-fold) was markedly increased in transgenic mice compared with non-transgenic littermates. The bile acid pool of CYP7A1 transgenic mice was doubled mainly due to increased hydrophobic dihydroxy bile acids. In CYP7A1 transgenic mice, livers contained approximately 3-fold more sterol response element-binding protein-2 mRNA. Hepatic expression of mRNAs encoding lipogenic enzymes (i.e. fatty-acid synthase, acetyl-CoA carboxylase, stearoyl-CoA desaturase, squalene synthase, farnesyl-pyrophosphate synthase, 3-hydroxy-3-methylglutaryl-CoA reductase, and low density lipoprotein receptor) as well as microsomal triglyceride transfer protein were elevated approximately 3-5-fold in transgenic mice. CYP7A1 transgenic mice also displayed a >2-fold increase in hepatic production and secretion of triglyceride-rich apoB-containing lipoproteins. Despite the increased hepatic secretion of apoB-containing lipoproteins in CYP7A1 mice, plasma levels of triglycerides and cholesterol were not significantly increased. These data suggest that the 5-fold increased expression of the low density lipoprotein receptor displayed by the livers of CYP7A1 transgenic mice was sufficient to compensate for the 2-fold increase production of apoB-containing lipoproteins. These findings emphasize the important homeostatic role that CYP7A1 plays in balancing the anabolic lipoprotein assembly/secretion pathway with the cholesterol catabolic bile acid synthetic pathway. |
| Increased production rates of LDL are common in individuals with low plasma levels of HDL cholesterol, independent of plasma triglyceride concentrations Ginsberg, H. N., C. Ngai, et al. (1993), Arterioscler Thromb 13(6): 842-51. Abstract: Reduced plasma levels of high density lipoprotein (HDL) cholesterol are associated with increased risk for coronary heart disease. Although plasma HDL levels are, in general, inversely related to plasma triglyceride (TG) concentrations, a small proportion of individuals with low HDL cholesterol concentrations have normal plasma TG levels. We wished to determine whether subjects with low plasma levels of HDL cholesterol could be characterized by common abnormalities of lipoprotein metabolism independent of plasma TGs. Therefore, we studied the metabolism of low density lipoprotein (LDL) apolipoprotein B (apo B) and HDL apolipoprotein A-I (apo A-I) in subjects with low plasma HDL cholesterol concentrations with or without hypertriglyceridemia. Nine subjects with low plasma HDL cholesterol levels and normal levels of plasma TGs and LDL cholesterol were studied. Autologous 131I-LDL and 125I-HDL were injected intravenously, and blood samples were collected for 2 weeks. LDL apo B and HDL apo A-I levels were measured by specific radioimmunoassays. Fractional catabolic rates (FCRs, pools per day) and production rates (PRs, milligrams/kilogram.day) for each apolipoprotein were determined. The results were compared with those obtained previously in nine subjects with low plasma HDL cholesterol levels and hypertriglyceridemia and in seven normal subjects. The normal subjects had an HDL apo A-I FCR (mean +/- SD) of 0.21 +/- 0.04. Despite large differences in plasma TG levels, the HDL apo A-I FCRs were similar in the low-HDL, normal-TG group (0.30 +/- 0.09) and the low-HDL, high-TG group (0.33 +/- 0.10), although only the latter value was significantly increased versus control subjects (p < 0.03). Increased apo A-I FCRs were associated with reduced HDL apo A-I levels in both groups of patients. Apo A-I PRs were similar in all groups. In contrast, LDL apo B PR was increased approximately 50% in the low-HDL, normal-TG group (19.3 +/- 6.6; p < 0.01) compared with normal subjects (12.5 +/- 2.6). There was a strong trend toward a greater LDL apo B PR in the low-HDL, high-TG group (17.6 +/- 4.5; p = 0.06 versus normal subjects) as well. LDL apo B FCRs were similar in all three groups. LDL apo B concentrations were also increased in the group with low HDL cholesterol and normal TG levels. Both groups with low HDL cholesterol levels had cholesterol-depleted LDL and HDL particles.(ABSTRACT TRUNCATED AT 400 WORDS) |
| Increased proximal tubular cholesterol content: implications for cell injury and "acquired cytoresistance" Zager, R. A., K. M. Burkhart, et al. (1999), Kidney Int 56(5): 1788-97. Abstract: BACKGROUND: Acute renal failure (ARF) leads to secondary adaptive changes that serve to protect proximal tubules from subsequent ischemic or toxic damage so-called "acquired cytoresistance" (CR). A characteristic of CR is increased plasma membrane resistance to attack. Therefore, this study sought to identify potential changes in plasma membrane lipid composition in CR tubules/renal cortex and, if present, to test whether they might mechanistically contribute to the CR state. METHODS: Renal cortices/isolated tubules were obtained from CR mouse kidneys (18-hr postinduction of ischemia reperfusion, myoglobinuria, or ureteral obstruction). Their plasma membrane phospholipid/cholesterol profiles were compared with those observed in either control tissues or tissues obtained one to two hours post-renal damage (that is, prior to emergence of CR). RESULTS: Either no changes or inconsistent changes in phospholipid profiles were observed in CR tissues. Conversely, CR (vs. control) tissues demonstrated a consistent 25 to 50% increase in membrane cholesterol content. To ascertain whether cholesterol impacts tubule susceptibility to injury, its levels were reduced in proximal tubule (HK-2) cells with either (a) mevastatin, (b) a cholesterol "stripping" agent, (c) cholesterol oxidase, or (d) cholesterol esterase. Then cell susceptibility to injury adenosine 5'-triphosphate (ATP) depletion; Fe-mediated oxidant stress was assessed. In each instance, cholesterol reductions dramatically sensitized to superimposed injury (for example, a 2 to 3 times increase in the % of lactate dehydrogenase release). When cholesterol levels were restored to normal in CR tubules (with a "stripping" agent), an increased tubule susceptibility to injury resulted. Because cholesterol decreases membrane fluidity, the impact of a membrane-fluidizing agent (A2C) on cell injury was assessed. A2C dramatically sensitized HK-2 cells to superimposed attack. CONCLUSIONS: ARF leads to an up-regulation of proximal tubule cholesterol content. The latter may then contribute to acquired CR, possibly by stabilizing the plasma membrane via its antifluidizing effect. |
| Increased resistance to ischaemic injury in the isolated perfused atherosclerotic heart of the cholesterol-fed rabbit Le Grand, B., B. Vie, et al. (1995), Cardiovasc Res 30(5): 689-96. Abstract: OBJECTIVE: In isolated, Langendorff-perfused hearts in the early stages of atherosclerosis from rabbits exposed to hypercholesterolaemia induced by 2% cholesterol feeding for 6 weeks (n = 23), and age-matched normal controls fed standard chow (n = 12), we studied baseline cardiac haemodynamics and the susceptibility of these hearts to 30 min global, normothermic ischaemia and 90 min reperfusion. METHODS: Spontaneously beating hearts were perfused with oxygenated Krebs buffer (pH 7.4) at constant pressure, and were enclosed in a thermostated water jacket at 37 degrees C. Isovolumetric left ventricular (LV) pressure was measured by means of a balloon placed in the LV cavity. An electromagnetic flow probe placed around the perfusion cannula determined coronary flow. At the end of an initial 30 min stabilisation period, several baseline cardiodynamic variables were measured, just before subjecting the hearts to 30 min ischaemia. Recovery of mechanical function and lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities in the coronary effluent were recorded throughout 90 min reperfusion. RESULTS: Baseline spontaneous heart rate, LV developed pressure (LVDP), coronary flow and pressure-rate index (PRI) were all significantly lower in hearts from cholesterol-fed rabbits (CFR) than in age-matched controls (P < 0.01). Although large differences in several baseline haemodynamic parameters in hearts from CFR and controls were evident before ischaemia, no statistically significant differences were discernible in these parameters between the two groups from 60 min reperfusion onwards (p = NS). Furthermore, CPK and, to a lesser extent, LDH release during reperfusion was attenuated in hearts from CFR compared to controls. CONCLUSIONS: Hearts from CFR exhibited markedly improved recovery upon reperfusion compared to age-matched controls, strongly suggesting increased myocardial resistance to ischaemic injury. |
| Increased response to cholesterol feeding in apolipoprotein C1-deficient mice van Ree, J. H., M. H. Hofker, et al. (1995), Biochem J 305 (Pt 3): 905-11. Abstract: The function of apolipoprotein (apo) C1 in vivo is not well understood. From in vitro studies it has been reported that an excess of apoC1 relative to apoE inhibits receptor-mediated uptake of remnant lipoproteins Sehayek and Eisenberg (1991) J. Biol. Chem. 266, 22453-22459. In order to gain a better understanding of the role of apoC1 in lipoprotein metabolism in vivo, we have generated apoC1-deficient mice by gene targeting in embryonic stem cells. Homozygous mutant mice are viable and do not show overt abnormalities. Serum triacylglycerol levels are increased by 60% on both a standard mouse diet and a mild hypercholesterolaemic diet compared with controls. Total serum cholesterol levels are similar to controls on the two diets. However, the level of high-density lipoprotein cholesterol in the apoC1-deficient mice fed on the mild hypercholesterolaemic diet is slightly decreased, which is accompanied by a 3-fold increase in very-low-density plus low-density lipoprotein (VLDL+LDL) cholesterol. On a severe atherogenic diet, the homozygous apoC1-deficient mice become hypercholesterolaemic, with a serum cholesterol level of 10.7 +/- 3.3 mM compared with 6.7 +/- 1.8 mM and 5.1 +/- 1.6 mM in heterozygous and control mice respectively. The increase in cholesterol is mainly confined to the VLDL+LDL-sized fractions. Binding experiments revealed that lipoproteins lacking apoC1 with d < 1.006 g/ml are poor competitors for 125I-labelled LDL binding to the LDL receptor on HepG2 cells. This suggests that total apoC1 deficiency leads to impaired receptor-mediated clearance of remnant lipoproteins rather than enhanced uptake, as was expected from data reported in the literature. |
| Increased reverse cholesterol transport in athletes Gupta, A. K., E. A. Ross, et al. (1993), Metabolism 42(6): 684-90. Abstract: Proposed mechanisms for the cardioprotective benefits of exercise include decreased lipid deposition and increased reverse cholesterol transport (RCT). RCT involves the efflux of tissue free cholesterol into high-density lipoprotein (HDL) particles, esterification by lecithin:cholesterol acyltransferase (LCAT), transfer to other lipoproteins by cholesterol ester transfer proteins (CETP), and liver excretion. We tested the hypothesis that RCT is enhanced in athletes and that this can occur without large increases in plasma HDL cholesterol (HDL-C) mass levels. Fasting venous blood was drawn from 13 sedentary men and 11 athletes exercising at the rate of 5,185 +/- 501 kcal/wk. Compared with controls, athletes had similar age, body mass index (BMI), HDL-C (P >.1) and apolipoprotein (apo) A-1 (P >.5) levels, and lower low-density lipoprotein cholesterol (LDL-C) (P <.05) and apo B (P <.03) levels. The net mass of free cholesterol transported (NMCT) out of cultured human fibroblasts into the athletes' serum was greater than that for controls (25.5 +/- 8.0 v 7.1 +/- 2.6 micrograms/mL/h, P =.048). The efflux component of this transport correlated with HDL-C and apo A-1 levels and was similar between groups (P =.24), suggesting that athletes' antiatherogenic NMCT findings were due to decreased cholesterol influx into the cells. Athletes had increased plasma LCAT (20.3 +/- 2.1 v 13.9 +/- 1.5 micrograms/mL/h, P =.028) and CETP activities (69.7 +/- 4.5 v 21.5 +/- 4.8%/mL/h, P <.001). The NMCT positively correlated with CETP and LCAT activities and inversely with apo B levels and the cardiac risk ratio apo B/A-1.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Increased risk of coronary heart disease death in men with low total and low-density lipoprotein cholesterol in the Russian Lipid Research Clinics Prevalence Follow-up Study Shestov, D. B., A. D. Deev, et al. (1993), Circulation 88(3): 846-53. Abstract: BACKGROUND. A continuously increasing risk of coronary heart disease with increasing levels of cholesterol has been reported by many observational and experimental studies. However, this type of association has not been observed in studies in the Russian Lipid Research Clinics. METHODS AND RESULTS. Twelve-year coronary heart disease mortality among 40- to 59-year-old men was analyzed in the Moscow and St Petersburg examines in the Russian Lipid Research Clinics Program. The baseline survey examined 6431 men fasting and free of prevalent coronary heart disease. Lipids and lipoproteins, blood pressure, body mass, education level, alcohol intake, and smoking history were obtained. Mortality follow-up was based on contacts with participants or their relatives or neighbors. Coronary heart disease mortality was analyzed based on risk factor levels and was further divided into rapid and nonrapid deaths. A J-shaped cholesterol-coronary heart disease risk function was present for both total and low-density lipoprotein cholesterol. Further examination showed hypocholesterolemic men to have lower low-density and higher high-density lipoprotein cholesterol, higher alcohol consumption, leaner body mass, and less education than men with normal or high cholesterol levels. When education level was considered, the J-shaped risk function was present only among men with less than a high school education. When deaths were classified into rapid (less than 24 hours after onset of symptoms) and nonrapid, the J-shaped risk function was restricted to rapid deaths. CONCLUSIONS. The results of disclose a sizeable subset of hypocholesterolemics in this population at increased risk of cardiac death associated with lifestyle characteristics. |
| Increased risk of death from coronary heart disease in men with low blood concentration of total cholesterol and low density lipoprotein cholesterol according to data from a prospective epidemiologic study in Moscow and Leningrad within the framework of Soviet-American cooperation Oganov, R. G., D. B. Shestov, et al. (1991), Ter Arkh 63(1): 6-11. Abstract: The authors provide the results of a prospective study carried out for almost 10 years among men who underwent screenings in 1975-1977 at an age of 40-59 years in Moscow and Leningrad (overall 6431 persons) with a purpose of analyzing potential causes of high risk of death from coronary heart disease in a group of subjects with hypocholesterolemia. Based on a mathematical-statistical analysis, variants of the interpretations of the indicated fact are presented. |
| Increased risk of myocardial infarction in men with both hypertriglyceridemia and elevated HDL cholesterol von Eckardstein, A., H. Schulte, et al. (1999), Circulation 99(14): 1925. |
| Increased saturation of the fatty acids in the sn-2 position of phospholipids reduces cholesterol crystallization in model biles Ringel, Y., G. J. Somjen, et al. (1998), Biochim Biophys Acta 1390(3): 293-300. Abstract: Changes in the molecular structure of biliary phospholipids were shown to have major effects on cholesterol solubility, carriers and crystallization in human and model biles. This study investigated systematically the effects of varying saturation of the phosphatidylcholine (PC) sn-2 fatty acid on the cholesterol crystallization process in 3 different model biles. Twenty % of the egg PC (EPC) in these biles were replaced by synthetic PC's with 16:0-18:0, 16:0-18:1, or 16:0-18:2 fatty acyl chains. With 18:0 in the sn-2 position, the crystal observation time (COT) was prolonged from 2 days in the control EPC solution to 14 days (p<0.05). The crystal growth rate (CGR) was reduced from 0.1 OD/day to unmeasurable levels, and the total crystal mass on day 14 decreased by 86%. The introduction of one (18:1), and two (18:2) double bonds in the sn-2 fatty acid rapidly reversed these effects. Ultracentrifugal analysis showed precipitable cholesterol as monohydrate crystals. In the 16:0-18:0 test solution, most of the precipitable cholesterol remained in the supersaturated multilamellar vesicles. Saturation of the biliary PC sn-2 fatty acyl chain prolongs the COT, slows the CGR, reduces the crystal mass, and extends cholesterol solubility in multilamellar vesicles. Desaturation of the sn-2 fatty acid reverses these effects. |
| Increased secretion of gelatinases A and B from the aortas of cholesterol fed rabbits: relationship to lesion severity Zaltsman, A. B. and A. C. Newby (1997), Atherosclerosis 130(1-2): 61-70. Abstract: Basement membrane degrading metalloproteinases (gelatinases) have been implicated in the regulation of vascular smooth muscle cell migration and proliferation in culture and during neointima formation in vivo. We compared the expression and activation of gelatinases A and B in explants derived from the arch, mid and distal portions of thoracic aortas of normal rabbits and those given a 1% cholesterol-containing diet for 8 weeks. Neointimal/medial ratio was less than 0.01 in normal rabbits but was significantly increased by cholesterol feeding in the arch (1.08 +/- 0.26), mid (0.75 +/- 0.28) and distal (0.32 +/- 0.12) portions of the aorta (mean +/- S.E.M., n = 6), and to a significantly (P < 0.05) greater extent in the arch and mid than distal portions. Secretion of gelatinase B measured by densitometric scanning of zymograms was undetectable from normal aortas, but was significantly increased by cholesterol feeding in the arch (0.16 +/- 0.06), mid (0.26 +/- 0.08) and distal (0.11 +/- 0.05) portions (optical density units, n = 6, each P < 0.05 versus normal diet). The increase in gelatinase B expression was localised by in situ hybridisation to neointimal vascular smooth muscle cells, macrophages and endothelial cells. Secretion of pro-gelatinase A was detected from normal aortas; it was increased by cholesterol feeding from the arch (4.0 versus 2.8, P < 0.05) and mid (3.6 versus 2.8, P < 0.05) but not distal portions of the aorta (1.8 versus 1.2, n.s.). Similar results were obtained for active gelatinase A secretion from the arch (0.50 versus 0.28, P < 0.05) and mid (0.47 versus 0.23, P < 0.05) but not distal portions (0.19 versus 0.20, n.s.). Increases in pro- and active gelatinase A secretion therefore paralleled the severity of atheroma formation. The results imply that increased basement membrane turnover mediated by gelatinases occurs during cholesterol induced atherosclerosis formation. |
| Increased secretion of tissue inhibitors of metalloproteinases 1 and 2 from the aortas of cholesterol fed rabbits partially counterbalances increased metalloproteinase activity Zaltsman, A. B., S. J. George, et al. (1999), Arterioscler Thromb Vasc Biol 19(7): 1700-7. Abstract: The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) plays an important role in extracellular matrix turnover and thereby modulates atherosclerotic plaque development. MMP-1, -2, -3, and -9 activity is increased by atherosclerosis, but the status of TIMPs is less clear. We therefore compared secretion of TIMPs-1 and -2 from cultured aortic explants derived from arch, middle, and distal portions of thoracic aortas of normal rabbits and rabbits fed a 1% cholesterol diet for 8 weeks, using reverse zymography of conditioned media. Cholesterol feeding significantly increased secretion of TIMP-1 from arch and middle portions (both 2.6-fold), accompanied by 2.0- and 2.7-fold increases in TIMP-2, respectively. Atherosclerotic aortas exhibited increased immunoreactive TIMP-1 and TIMP-2 in endothelial cells, smooth muscle cells, and macrophages. Staining of extracellular matrix was also prominent within the noncellular boundary region between fibrous cap and the lipid core, and within the lipid core. Increased TIMP-2 staining was also found in the media subjacent to the lipid core. In situ gelatin zymography demonstrated excess MMP activity within the plaque with partial inhibition in the lipid core base and subjacent media, consistent with the distribution of TIMPs. Casein zymography and in situ zymography demonstrated that increased caseinolytic activity was confined to the pericellular zones of macrophages within the lipid core, again consistent with its restriction by TIMPs. In summary, atherosclerosis increases TIMP expression, which counterbalances, in part, increased MMP activity. |
| Increased secretion of triglyceride and cholesterol following inhibition of long-chain fatty acid oxidation in rat liver Yamamoto, K., N. Fukuda, et al. (1996), Ann Nutr Metab 40(3): 157-64. Abstract: The effects of emeriamine, a fungal metabolite and a potent inhibitor of mitochondrial fatty acid oxidation, on ketogenesis and lipid secretion were examined in isolated perfused livers from 2-day-fasted rats. Liver perfusion with increasing concentrations of emeriamine up to 3 mumol caused a dose-dependent inhibition of ketone body production. The hepatic uptake of exogenous oleic acid substrate was comparable in the control and emeriamine-treated livers. The addition of 2 mumol emeriamine to the perfusion medium at either the beginning of perfusion or 2 h later caused immediate and almost complete cessation of ketone body production, which was accompanied by a concomitant decrease in the beta-hydroxybutyrate: acetoacetate ratio, suggesting a decreased production of NADH via mitochondrial beta-oxidation. Conversely, both triglyceride and cholesterol secretions were elevated, indicating a reciprocal response in ketogenesis and lipid secretion by the livers. The proportion of oleate in the perfusate triglyceride obtained from emeriamine-treated livers was significantly higher than that from control livers. In the post-perfused liver triglyceride, oleate was progressively increased in the livers treated with the inhibitor 2 h after perfusion and at the beginning of perfusion, respectively. These results indicate that direct inhibition of fatty acid oxidation diverts the exogenous fatty acids to the esterification pathway, and subsequently stimulate the synthesis and secretion of triglyceride and cholesterol. The fatty acid oxidation rate in the liver is, therefore, a critical determinant for the synthesis and secretion of these lipid components. |
| Increased sensitivity to dietary cholesterol in diabetic and hypothyroid rats associated with low levels of hepatic HMG-CoA reductase expression Ness, G. C. and K. R. Gertz (2004), Exp Biol Med (Maywood) 229(5): 407-11. Abstract: We recently postulated that hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase functions as a cholesterol buffer to protect against the serum and tissue cholesterol raising action of dietary cholesterol. This postulate predicts that diminished basal expression of hepatic HMG-CoA reductase results in increased sensitivity to dietary cholesterol. Because diabetic and hypothyroid animals are known to have markedly reduced hepatic HMG-CoA reductase, these animals were selected as models to test our postulate. When rats were rendered diabetic with streptozotocin, their hepatic HMG-CoA reductase activity decreased from 314 to 22 pmol. min(-1). mg(-1), and their serum cholesterol levels increased slightly. When the diabetic animals were challenged with a diet containing 1% cholesterol, their serum cholesterol levels doubled, and their hepatic reductase activity decreased further to 0.9 pmol. min(-1). mg(-1). Hepatic low-density lipoprotein (LDL) receptor immunoreactive protein levels were unaffected in the diabetic rats whether fed cholesterol-supplemented diets or not. In rats rendered hypothyroid by thyroparathyroidectomy, serum cholesterol levels rose from 100 to 386 mg/dl in response to the 1% cholesterol challenge, whereas HMG-CoA reductase activity dropped from 33.8 to 3.4 pmol. min(-1). mg(-1). Hepatic LDL receptor immunoreactive protein levels decreased only slightly in the hypothyroid rats fed cholesterol-supplemented diets. Taken together, these results show that rats deficient in either insulin or thyroid hormone are extremely sensitive to dietary cholesterol largely due to low basal expression of hepatic HMG-CoA reductase. |
| Increased serum cholesterol in healthy human methane producers is confounded by age Fernandes, J., T. M. Wolever, et al. (1998), J Nutr 128(8): 1349-54. Abstract: It has been theorized that colonic production and absorption of short-chain fatty acids (SCFA) is different in methane producers (MP) compared with nonproducers (MNP). Because colonic SCFA may influence systemic lipid metabolism, blood lipids may differ in MP and MNP. To compare serum lipids and SCFA in fasting MP and MNP, we measured breath gases, serum lipids and SCFA in 167 healthy subjects and excluded subjects with abnormal blood lipids. The 66 MP were significantly older than the 63 MNP (49.5 +/- 16.0 vs. 39.6 +/- 17.0 y, P = 0.0009), and breath methane concentrations were weakly correlated with age in MP (r = 0.268, P = 0.03). Mean serum cholesterol was significantly higher in MP compared with MNP, but the differences were not significant after adjusting for age. No significant differences were observed in serum SCFA between the two groups. This study has shown that breath methane increases with age, which may be due to age-related increases in transit time and carbohydrate malabsorption. These results provide no conclusive link between colonic events and serum lipids in MP because, with age, methane production increased as did serum cholesterol. More research is required before any definite conclusions can be drawn. |
| Increased serum level of the acute inflammation phase parameter CRP and the high level of low density lipoprotein cholesterol--factors of increased risk of development of atherosclerosis and its complications (a literature review) Egorova, M. O. (2002), Klin Lab Diagn(6): 3-6. |
| Increased serum total cholesterol to HDL-cholesterol ratio after imipramine Yeragani, V. K., R. Pohl, et al. (1990), Psychiatry Res 32(2): 207-9. |
| Increased steroid hormone secretion in mouse Leydig tumor cells after induction of cholesterol translocation by sphingomyelin degradation Porn, M. I., J. Tenhunen, et al. (1991), Biochim Biophys Acta 1093(1): 7-12. Abstract: The effects of sphingomyelin degradation on 3Hcholesterol transfer from the cell surface to mitochondria were examined in mouse Leydig tumor cells. These cells were used since they utilize cholesterol for steroid hormone synthesis in the mitochondria, and also possess acyl-CoA: cholesterol acyl transferase (ACAT) activity in the endoplasmic reticulum. Exposure of glutaraldehyde-fixed mouse Leydig tumor cells to sphingomyelinase (50 mU/ml, 60 min) resulted in the degradation of about 50% of cell sphingomyelin, suggesting that only half of the sphingomyelin mass in these cells was located in the exoleaflet of the plasma membrane. The partial sphingomyelin degradation resulted in the translocation of cellular unesterified 3Hcholesterol from plasma membranes (cholesterol oxidase-susceptible) to intracellular compartments (oxidase-resistant). The fraction of 3Hcholesterol that was translocated, i.e., between 20 and 50%, varied with different 3Hcholesterol-labeling methods. Cholesterol translocation induced by sphingomyelin degradation subsequently led to the stimulation of ACAT activity, suggesting that a fraction of cell surface cholesterol was transported to the endoplasmic reticulum. The sphingomyelinase-induced 3Hcholesterol flow from the cell surface to the cell interior was also in part directed to the mitochondria, as evidenced by the increased secretion of 3Hsteroid hormones. In addition, the cyclic AMP-induced activation of steroidogenesis was further enhanced by the sphingomyelinase-induced cholesterol translocation. Based on the current results, it seems evident that a significant portion of the translocated 3Hcholesterol made its way from plasma membranes into the mitochondria for steroidogenesis. |
| Increased susceptibility of angiographically smooth left anterior descending coronary artery to an impairment of vasoresponse to acetylcholine, and the relation between impaired vasoresponse and low-density lipoprotein cholesterol level Kawashima, T., A. Yashiro, et al. (1995), Am J Cardiol 75(17): 1265-7. Abstract: In the present study, we demonstrated that the angiographically smooth LAD is more susceptible than the LC to an impairment of vasoresponse to acetylcholine, suggesting the more severe endothelial dysfunction in the LAD. We also showed that levels of LDL play a partial but important role on endothelial dysfunction. |