| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Differential effects of different dietary fats on enzymes regulating cholesterol storage in rat liver Bravo, E., L. Flora, et al. (1997), Biochem Soc Trans 25(1): 24S. |
| Differential effects of ergosterol and cholesterol on Cdk1 activation and SRE-driven transcription Suarez, Y., C. Fernandez, et al. (2002), Eur J Biochem 269(6): 1761-71. Abstract: Cholesterol is essential for cell growth and division, but whether this is just a consequence of its use in membrane formation or whether it also elicits regulatory actions in cell cycle machinery remains to be established. Here, we report on the specificity of this action of cholesterol in human cells by comparing its effects with those of ergosterol, a yeast sterol structurally similar to cholesterol. Inhibition of cholesterol synthesis by means of SKF 104976 in cells incubated in a cholesterol-free medium resulted in cell proliferation inhibition and cell cycle arrest at G2/M phase. These effects were abrogated by cholesterol added to the medium but not by ergosterol, despite that the latter was used by human cells and exerted similar homeostatic actions, as the regulation of the transcription of an SRE-driven gene construct. In contrast to cholesterol, ergosterol was unable to induce cyclin B1 expression, to activate Cdk1 and to resume cell cycle in cells previously arrested at G2. This lack of effect was not due to cytotoxicity, as cells exposed to ergosterol remained viable and, upon supplementing with UCN-01, an activator of Cdk1, they progressed through mitosis. However, in the presence of suboptimal concentrations of cholesterol, ergosterol exerted synergistic effects on cell proliferation. This is interpreted on the basis of the differential action of these sterols, ergosterol contributing to cell membrane formation and cholesterol being required for Cdk1 activation. In summary, the action of cholesterol on G2 traversal is highly specific and exerted through a mechanism different to that used for cholesterol homeostasis, reinforcing the concept that cholesterol is a specific regulator of cell cycle progression in human cells. |
| Differential effects of geometrical isomers of octadecadienoic acids on ketogenesis and lipid secretion in the livers from rats fed a cholesterol-enriched diet Fukuda, N., T. Etoh, et al. (1995), Ann Nutr Metab 39(3): 185-92. Abstract: The effect of cis,cis (cc)- and trans,trans (tt)-9,12-octadecadienoic (18:2) acids on ketogenesis and lipid secretion was compared in isolated perfused livers from cholesterol-fed rats. The hepatic uptake of 18:2 acids was comparable in both isomers. The livers perfused with cc-18:2 acid in comparison with those perfused without fatty acid substrate produced approximately 4-fold more ketone bodies accompanying the rise of the beta-hydroxybutyrate:acetoacetate ratio, while the tt-acid isomer further increased these parameters. The hepatic secretion rates of triglyceride and phospholipid as well as cholesterol were all elevated on perfusing the cc-18:2 acid as compared to without fatty acid. In contrast, the rates observed with the tt-18:2 acid isomer except for phospholipid were intermediate, indicating a reciprocal response in ketogenesis and lipid secretion by the trans isomer. The rate of incorporation of trans-fatty acid into perfusate triglyceride and cholesterol ester were lower than cis-acid, but vice versa into perfusate phospholipids. On the other hand, the effects of trans-fatty acid on the concentration and composition of hepatic lipids were less clear. These results emphasize the differential effect of geometrical isomers of the 18:2 acids on oxidation and esterification even in the livers containing a high level of cholesterol. |
| Differential effects of lecithin and cholesterol on the immunoreactivity and conformation of apolipoprotein A-I in high density lipoproteins Collet, X., B. Perret, et al. (1991), J Biol Chem 266(14): 9145-52. Abstract: Recently identified epitopes in apoA-I define a distinct N-terminal region with a complex tertiary structure, characterized by multiple discontinuous epitopes. Other epitopes are constituted of short domains centered either on beta-turns or random coils or on the 22-mer amphipathic alpha-helices (Marcel, Y. L., Provost, P. R., Koa, H., Raffai, E., Vu Dac, N., Fruchart, J.-C., and Rassart, E. (1991) J. Biol. Chem. 266, 3644-3653). The compared immunoreactivity of seven epitopes studies here in response first to delipidation of high density lipoprotein (HDL) apoA-I by detergents, and second to modifications of HDL lipid composition by phospholipase A2 or by enrichment in surface lipids demonstrates that apoA-I has a flexible conformation which is readily responsive to the nature and concentration of bound lipids and that the structure of lipid-free apoA-I is significantly different from that of HDL-bound apoA-I, possibly representing a condensed molecule with several masked domains. In HDL apoA-I, these epitopes define five distinct domains which are characterized by particular responses to lipid modifications. However, two domains, each starting at the N-terminal beta-turn of an amphipathic alpha-helical repeat (residues 99-121 and 186-209, respectively) have almost identical immunoreactivity whether after detergent treatment or after changes in cholesterol and phospholipid levels, a property which probably reflects the known periodicity of apoA-I structural 22-mers. The immunoreactivity of a discontinuous epitope, representative of the N-terminal domain, is inversely related to the concentration of phospholipids, a unique characteristic among the epitopes tested here which indicates that the complex N-terminal region interacts with phospholipids, either directly or indirectly. These studies demonstrate that the conformation of multiple domains of HDL apoA-I is dependent on lipid phase composition and differentially affected by cholesterol and phospholipids. |
| Differential effects of long-term renin-angiotensin system blockade on limitation of infarct size in cholesterol-fed rabbits Hoshida, S., N. Yamashita, et al. (2000), Atherosclerosis 149(2): 287-94. Abstract: We evaluated the effects of chronic inhibition of angiotensin-converting enzyme (ACE) or receptor blockade of angiotensin II type I on the size of myocardial infarcts induced by coronary occlusion-reperfusion in rabbits fed a high-cholesterol or normal diet for 10 weeks. In treated rabbits, myocardial infarction occurred 24 h after the last dose of enalapril or L-158809, an angiotensin II type I receptor antagonist, because of the drugs' waning effects on hemodynamic parameters. The size of the infarct was significantly larger in cholesterol-fed rabbits than in rabbits fed a normal diet. This augmentation of infarct size in cholesterol-fed rabbits was reversed by long-term treatment with enalapril, but not L-158809. The favorable effects of enalapril treatment disappeared after pretreatment with the bradykinin B(2) receptor blocker HOE 140. Long-term enalapril or L-158809 administration did not reduce the size of the infarct in rabbits fed a normal diet. ACE activity in ischemic myocardium significantly exceeded that in nonischemic myocardium and was further increased in cholesterol-fed rabbits, but was significantly reduced by long-term enalapril, but not L-158809. Moreover, treatment with enalapril, but not L-158809, restored acetylcholine-induced endothelium-dependent relaxation of aortic rings from cholesterol-fed rabbits. These results demonstrate that long-term ACE inhibition, but not angiotensin II type I receptor blockade, effectively reduces the size of myocardial infarcts in cholesterol-fed rabbits. The favorable effects of enalapril treatment may involve primarily a bradykinin B(2) receptor-mediated pathway. |
| Differential effects of lovastatin on the trafficking of endogenous and lipoprotein-derived cholesterol in human monocyte-derived macrophages Cignarella, A., B. Brennhausen, et al. (1998), Arterioscler Thromb Vasc Biol 18(8): 1322-9. Abstract: Lovastatin has been shown to reduce cholesterol esterification in cholesterol-loaded human macrophages. Surprisingly, in nonloaded macrophages, lovastatin produces the opposite effect, lowering free cholesterol and increasing cholesteryl ester levels, as measured by high-performance liquid chromatography. In cholesterol-loaded cells, lovastatin reduced the cholesteryl esters of unsaturated but not those of saturated fatty acids. In nonloaded cells, by contrast, the cholesteryl esters of unsaturated fatty acids tended to increase after lovastatin treatment. Total (free plus esterified) cellular cholesterol content in nonloaded cells fell by 18% with 12-micromol/L lovastatin treatment but did not change in cholesterol-loaded cells. Lovastatin had no effect on the binding or uptake of acetylated low density lipoprotein, acyl coenzyme A:cholesterol acyltransferase (ACAT) activity, the secretion of 3Hcholesterol into the medium, or lysosomal hydrolysis of cholesteryl esters. Apolipoprotein (apo) E mRNA levels increased but apoE secretion into the medium decreased with lovastatin treatment in both cholesterol-loaded and nonloaded cells. Cholesterol of exogenous origin has been shown to pass via the cell membrane before its esterification by ACAT. We postulate that this is not the case for endogenous cholesterol, which may have direct access to ACAT. Our findings therefore suggest that lovastatin hinders the delivery of intracellular cholesterol to the plasma membrane, resulting in increased free cholesterol and lower levels of cholesteryl ester in cholesterol-loaded cells. In nonloaded cells, virtually all cholesterol is of endogenous origin and is normally translocated to the cell membrane. Lovastatin prevents this process, thus shunting newly synthesized cholesterol toward esterification and leading to an increase in the concentration of cholesteryl esters, even in the face of a drop in total and free cholesterol levels. Intracellular apoE may play a role in this process. |
| Differential effects of lovastatin treatment on brain cholesterol levels in normal and apoE-deficient mice Eckert, G. P., C. Kirsch, et al. (2001), Neuroreport 12(5): 883-7. Abstract: Growing evidence indicates that membrane cholesterol is involved in the development of Alzheimer's disease. Therefore, the availability of pharmacological strategies to modify brain cholesterol is of increasing importance. Accordingly, we investigated the effects of the HMG-CoA reductase inhibitor lovastatin on brain cholesterol levels in vivo. Brain cholesterol was significantly decreased by lovastatin treatment (100 mg/kg/day) in 1- and 12-month-old C57BL/6J mice. Reduced brain cholesterol was associated with decreased pyrene-excimer fluorescence, indicating altered membrane function. Lovastatin had no effect on brain cholesterol ApoE-/- mice. Peripheral cholesterol levels were not affected by lovastatin in all three groups of mice. We demonstrate for the first time that lovastatin represents a valid pharmacological tool to significantly modulate brain cholesterol levels. |
| Differential effects of mixtures of cholesterol oxidation products on bovine aortic endothelial cells and human monocytic U937 cells O'Sullivan A, J., C. O'Callaghan Y, et al. (2005), Int J Toxicol 24(3): 173-9. Abstract: Cholesterol oxidation products or oxysterols are of interest due to their hypothesized role in the development of atherosclerosis. The objective of the present study was to assess the cytotoxic effects of mixtures of oxysterols: 25-hydroxycholesterol (25-OHC), 7beta-hydroxycholesterol (7beta -OHC), and cholesterol-5beta,6beta -epoxide (beta -epox) on two cell types associated with the atherosclerotic process, bovine aortic endothelial (BAE) cells and human monocytic U937 cells. Cells were exposed to 25-OHC, 7beta -OHC, or beta -epox, or equimolar mixtures (30 mu M) of 25-OHC and 7beta -OHC, 25-OHC and beta-epox, or 7beta-OHC and beta -epox for 48 h. Cell viability was assessed using the fluorescein diacetate/ethidium bromide (FDA/ EtBr) assay and nuclear morphology following staining with Hoechst 33342. 25-OHC was the least toxic of the oxysterols and did not induce apoptosis in either cell line. Both 7beta-OHC and beta -epox treatments were cytotoxic and induced apoptosis in the cells. Cotreatment with 25-OHC did not alter the toxicity of 7beta -OHC and beta -epox in U937 cells but did decrease the percentage apoptotic cell death. In contrast, in the BAE cells cotreatment with 25-OHC had a slight protective effect on 7beta -OHC and beta-epox-induced toxicities and a marked decrease in apoptotic cell death. The 7beta -OHC and beta -epox mixture induced a significant increase in apoptotic cell death in U937 cells but decreased this mode of cell death in the BAE cells. The effects of oxysterols on glutathione levels also differed between the cells with changes noted in U937 and not in BAE cells. Results demonstrate interactive effects when oxysterols are studied as mixtures rather than single compounds in vitro. |
| Differential effects of modification of membrane cholesterol and sphingolipids on the conformation, function, and trafficking of the G protein-coupled cholecystokinin receptor Harikumar, K. G., V. Puri, et al. (2005), J Biol Chem 280(3): 2176-85. Abstract: The lipid microenvironment of receptors can influence their conformation, function, and regulation. Cholecystokinin (CCK)-stimulated signaling is abnormal in some forms of hyperlipidemia, suggesting the possibility of unique sensitivity to its lipid environment. Here we examined the influence of cholesterol and sphingolipids on CCK receptors in model Chinese hamster ovary cell systems having lipid levels modified. Cholesterol was modulated chemically or metabolically, and sphingolipids were modulated using a temperature-sensitive cell line (SPB-1). Receptor conformation was probed with a fluorescent full agonist ligand, Alexa 488-conjugated Gly-Nle(28,31)CCK-(26-33), shown previously to decrease in anisotropy and lifetime when occupying a receptor in the active conformation (Harikumar, K. G., Pinon, D. L., Wessels, W. S., Prendergast, F. G., and Miller, L. J. (2002) J. Biol. Chem. 277, 18552-18560). Anisotropy and lifetime of this probe were increased and prolonged with cholesterol enrichment, and decreased and shortened with depletion of cholesterol or sphingolipids. The increase in these parameters with cholesterol enrichment may reflect change in CCK receptor conformation toward its inactive, uncoupled state. Indeed, cholesterol enrichment resulted in nonproductive agonist ligand binding, with affinity of binding higher than normal and calcium signaling in response to this reduced. In cholesterol- and sphingolipid-depleted states, the receptor moved into conformations that were less than optimal. With cholesterol depletion, both ligand binding and signaling were decreased, yet internalization and trafficking were unperturbed. With sphingolipid depletion, ligand binding and signaling were normal, but internalization and trafficking were markedly inhibited. Of note, normal transferrin receptor trafficking through the same clathrin-dependent pathway was maintained under these conditions. Thus, lipid microenvironment of the CCK receptor is particularly important, with different lipids having distinct effects. |
| Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits Schuh, J. R., D. J. Blehm, et al. (1993), J Clin Invest 91(4): 1453-8. Abstract: To investigate the mechanism by which angiotensin-converting enzyme (ACE) inhibition attenuates atherogenesis, we have studied the effects of a non-sulfhydryl ACE inhibitor, enalapril, and an angiotensin receptor antagonist, SC-51316, in cholesterol-fed rabbits. After 3 mo of enalapril treatment (10 mg/kg per d, p.o.) the percent plaque areas in the thoracic aortas of treated animals were significantly reduced (controls: 86.8 +/- 3.5%; treated: 31.1 +/- 8%, P < 0.001). Aortic cholesterol content was also reduced (controls: 31.4 +/- 3.2 mg/g tissue; treated: 7.4 +/- 1.8 mg/g, P < 0.001). Enalapril had no significant effect on plasma lipid levels or conscious blood pressure. In a second study, the angiotensin II receptor antagonist SC-51316 was administered at a dose equivalent to enalapril at blocking angiotensin pressor effects in vivo (30 mg/kg per d, p.o.). Evaluation after 3 mo indicated no significant attenuation of aortic atherosclerosis. These results demonstrate that: (a) enalapril attenuates atherogenesis without affecting either blood pressure or plasma lipid levels; (b) antioxidant activity, found with sulfhydryl-containing ACE inhibitors, is not necessary for reducing plaque formation; and (c) the attenuation of atherogenesis by ACE inhibition may not be due to blockade of the renin-angiotensin system. Alternatively, one must consider the multiple effects of ACE inhibition on other hormone systems, such as bradykinin, or the possibility that alternate angiotensin II receptors may be involved in atherosclerosis. |
| Differential effects of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I are consistent across hypercholesterolemic patient subgroups Davidson, M. H., L. Ose, et al. (2003), Clin Cardiol 26(11): 509-14. Abstract: BACKGROUND: In addition to lowering plasma levels of low-density lipoprotein cholesterol (LDL-C), statins also raise high-density lipoprotein cholesterol (HDL-C). HYPOTHESIS: Recent studies have shown that treatment with simvastatin results in larger increases in HDL-C than those seen with atorvastatin. The results of three clinical studies are analyzed, comparing the effects of simvastatin and atorvastatin on HDL-C and apolipoprotein A-I (apo A-I) in the total cohort and in several subgroups of hypercholesterolemic patients. The three studies were all multicenter, randomized clinical trials that included simvastatin (20-80 mg) and atorvastatin (10-80 mg) treatment arms. The subgroup analyses performed were gender; age (< 65 and > or = 65 years); baseline HDL-C (male: < 40 or > or = 40 mg/dl; female: < 45 or > or = 45 mg/dl), baseline LDL-C (< 160 or > or = 160 mg/dl), and baseline triglycerides (< 200 or > or = 200 mg/dl). RESULTS: Both drugs produced similar increases in HDL-C levels at low doses; however, at higher drug doses (40 and 80 mg), HDL-C showed a significantly greater increase with simvastatin than with atorvastatin (p < 0.05 to < 0.001). Therefore, while HDL-C remained consistently elevated across all doses of simvastatin, there appeared to be a pattern of decreasing HDL-C with an increasing dose of atorvastatin. A similar negative dose response pattern was also observed with apo A-I in atorvastatin-treated patients, suggesting a reduction in the number of circulating HDL particles at higher doses. Both drugs reduced LDL-C and triglycerides in a dose-dependent fashion, with atorvastatin showing slightly greater effects. The differential effects of atorvastatin and simvastatin on HDL-C and apo A-I were observed for both the whole study cohorts and all subgroups examined; thus, no consistent treatment-by-subgroup interactions were observed. CONCLUSION: The data presented show that, across different hypercholesterolemic patient subgroups, simvastatin increases HDL-C and apo A-I more than atorvastatin at higher doses, with evidence of a negative dose response effect on HDL-C and apo A-I with atorvastatin, but not simvastatin. |
| Differential effects of sphingomyelin hydrolysis and cholesterol transport on oxysterol-binding protein phosphorylation and Golgi localization Ridgway, N. D., T. A. Lagace, et al. (1998), J Biol Chem 273(47): 31621-8. Abstract: The deposition of de novo synthesized and lipoprotein-derived cholesterol at the plasma membrane and transport to the endoplasmic reticulum is dependent on sphingomyelin (SM) content. Here we show that hydrolysis of plasma membrane SM in Chinese hamster ovary cells by exogenous bacterial sphingomyelinase resulted in enhanced cholesterol esterification at the endoplasmic reticulum and rapid dephosphorylation of the oxysterol-binding protein (OSBP), a cytosolic/Golgi receptor for oxysterols such as 25-hydroxycholesterol. After sphingomyelinase treatment, restoration of OSBP phosphorylation closely paralleled resynthesis of SM and down-regulation of cholesterol ester synthesis. SM hydrolysis activated an okadaic acid-sensitive phosphatase that was not stimulated in Chinese hamster ovary cells by short chain ceramides. Agents that specifically blocked sphingomyelinase-mediated delivery of cholesterol to acyl-CoA:cholesterol acyltransferase (U18666A) or promoted cholesterol efflux to the medium (cyclodextrin) did not inhibit OSBP dephosphorylation. SM hydrolysis also promoted OSBP translocation from a vesicular compartment to the Golgi apparatus. Cyclodextrin and U18666A also caused OSBP translocation to the Golgi apparatus, suggesting that OSBP movement is coupled to changes in the cholesterol content of the plasma membrane or Golgi apparatus. These results identify OSBP as a potential target of SM turnover and cholesterol mobilization at the plasma membrane and/or Golgi apparatus. |
| Differential effects of ursodeoxycholic acid and ursocholic acid on the formation of biliary cholesterol crystals in mice Uchida, K., T. Akiyoshi, et al. (1991), Lipids 26(7): 526-30. Abstract: The preventive effect of 3 alpha, 7 beta, 12 alpha-trihydroxy-5 beta-cholanoic acid (ursocholic acid) and ursodeoxycholic acid on the formation of biliary cholesterol crystals was studied in mice. Cholesterol crystals developed with 80% incidence after feeding for five weeks a lithogenic diet containing 0.5% cholesterol and 0.25% sodium cholate. When 0.25% ursocholic acid or ursodeoxycholic acid was added to the lithogenic diet, the incidence as well as the grade (severity) of the gallstones were reduced. Plasma and liver cholesterol levels were decreased by ursodeoxycholic acid but not by ursocholic acid. Gallbladder cholesterol and phospholipid levels were decreased by both bile acids. The biliary bile acid level was decreased by ursocholic acid but not by ursodeoxycholic acid. After feeding ursocholic acid, its level in the bile was about 25% and the levels of cholic acid and beta-muricholic acid decreased. Fecal sterol excretion was not changed by ursocholic acid, but was increased by ursodeoxycholic acid. After feeding ursocholic acid, fecal excretion of deoxycholic acid, cholic acid, and ursocholic acid increased. No differences were found between mice, with or without gallstones, in plasma and liver cholesterol levels, biliary phospholipid and bile acid levels, fecal sterol and bile acid levels, and biliary and fecal bile acid composition. The results suggest that the lower incidence of crystal formation after treatment with ursocholic acid is probably by a different mechanism than with ursodeoxycholic acid. In the mouse model, ursodeoxycholic acid exerts its effect at least partially, by decreasing cholesterol absorption. Ursocholic acid is well absorbed and excreted into bile and transformed into deoxycholic acid by the intestinal microflora in mice. |
| Differential expression of cholesterol hydroxylases in Alzheimer's disease Brown, J., 3rd, C. Theisler, et al. (2004), J Biol Chem 279(33): 34674-81. Abstract: Cholesterol is eliminated from neurons by oxidization, which generates oxysterols. Cholesterol oxidation is mediated by the enzymes cholesterol 24-hydroxylase (CYP46A1) and cholesterol 27-hydroxylase (CYP27A1). Immunocytochemical studies show that CYP46A1 and CYP27A1 are expressed in neurons and some astrocytes in the normal brain, and CYP27A1 is present in oligodendrocytes. In Alzheimer's disease (AD), CYP46A1 shows prominent expression in astrocytes and around amyloid plaques, whereas CYP27A1 expression decreases in neurons and is not apparent around amyloid plaques but increases in oligodendrocytes. Although previous studies have examined the effects of synthetic oxysterols on the processing of amyloid precursor protein (APP), the actions of the naturally occurring oxysterols have yet to be examined. To understand the role of cholesterol oxidation in AD, we compared the effects of 24(S)- and 27-hydroxycholesterol on the processing of APP and analyzed the cell-specific expression patterns of the two cholesterol hydroxylases in the human brain. Both oxysterols inhibited production of Abeta in neurons, but 24(S)-hydroxycholesterol was approximately 1000-fold more potent than 27-hydroxycholesterol. The IC(50) of 24(S)-hydroxycholesterol for inhibiting Abeta secretion was approximately 1 nm. Both oxysterols induced ABCA1 expression with IC(50) values similar to that for inhibition of A beta secretion, suggesting the involvement of liver X receptor. Oxysterols also inhibited protein kinase C activity and APP secretion following stimulation of protein kinase C. The selective expression of CYP46A1 around neuritic plaques and the potent inhibition of APP processing in neurons by 24(S)-hydroxycholesterol suggests that CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease. |
| Differential gene regulation of StarD4 and StarD5 cholesterol transfer proteins. Activation of StarD4 by sterol regulatory element-binding protein-2 and StarD5 by endoplasmic reticulum stress Soccio, R. E., R. M. Adams, et al. (2005), J Biol Chem 280(19): 19410-8. Abstract: The StarD4 and StarD5 proteins share approximately 30% identity, and each is a steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain. We previously showed StarD4 expression is sterol-repressed, consistent with regulation by sterol regulatory element-binding proteins (SREBPs), whereas StarD5 is not sterol-regulated. Here we further address the regulation and function of StarD4 and StarD5. Unlike StAR, the START family prototype, StarD4 and StarD5 were not induced by steroidogenic stimuli in Leydig cells. However, StarD4 and StarD5 showed StAR-like activity in a cell culture steroidogenesis assay, indicating cholesterol transfer. In transgenic mice expressing active SREBPs, StarD4 was predominantly activated by SREBP-2 rather than SREBP-1a. The mouse and human StarD4 proximal promoters share approximately 70% identity, including several potential sterol regulatory elements (SREs). Reporters driven by the StarD4 promoter from either species were transfected into NIH-3T3 cells, and reporter activity was highly repressed by sterols. Site-directed mutagenesis of potential SREs identified a conserved functional SRE in the mouse (TCGGTCCAT) and human (TCATTCCAT) promoters. StarD5 was not sterol-repressed via SREBPs nor was it sterol-activated via liver X receptors (LXRs). Even though StarD4 and StarD5 were not LXR targets, their overexpression stimulated LXR reporter activity, suggesting roles in cholesterol metabolism. StarD5 expression increased 3-fold in free cholesterol-loaded macrophages, which activate the endoplasmic reticulum (ER) stress response. When NIH-3T3 cells were treated with agents to induce ER stress, StarD5 expression increased 6-8-fold. Because StarD4 is regulated by sterols via SREBP-2, whereas StarD5 is activated by ER stress, they likely serve distinct functions in cholesterol metabolism. |
| Differential hepatic and renal cholesterol levels in diabetes-prone BHE/cdb rats fed menhaden oil or beef tallow Wickwire, K., M. Porter, et al. (1997), Proc Soc Exp Biol Med 214(4): 346-51. Abstract: A series of experiments were conducted to determine whether the feeding of beef tallow compared with menhaden oil would affect renal cortex membrane composition, Na,K-ATPase activity, renal cholesterol uptake, and plasma lipoprotein cholesterol profile. BHE/cdb rats were used because they carry a genetic trait for non-insulin-dependent diabetes mellitus and are prone to develop diabetic nephropathy. Beef tallow feeding resulted in an increase in HDL cholesterol and an increase in Na,K-ATPase activity. The different fats also affected the arachidonic acid content of the membrane but not the membrane cholesterol content. These diet effects may explain why the development of renal disease in beef tallow-fed rats is delayed when compared with rats fed an equivalent amount of menhaden oil. |
| Differential incorporation of cholesterol and cholesterol derivatives into ecdysteroids by the larval ring glands and adult ovaries of Drosophila melanogaster: a putative explanation for the l(3)ecd1 mutation Warren, J. T., J. S. Bachmann, et al. (1996), Insect Biochem Mol Biol 26(8-9): 931-43. Abstract: Studies in vitro revealed that intact ring glands of Drosophila melanogaster convert tritiated cholesterol (C) and 25-hydroxycholesterol (25C) via 7-dehydrocholesterol (7dC) and 7-dehydro-25-hydroxycholesterol (7d25C), respectively, to ecdysone (E) and 2-deoxyecdysone (2dE), while both intact and homogenized ovaries synthesize only 2dE from these precursors. Emulsified 7d25C was incorporated directly into ecdysteroids by these tissue preparations at a much greater rate than was 7d25C made in situ from 25C. To probe the basis of the biochemical defect in the ecdysteroid deficient conditional mutant ecdysoneless (ecd1), the differential incorporation into ecdysteroids of C (via 7dC), and particularly of 25C (via 7d25C), was measured relative to that observed after the incubation of 7d25C directly with both wild type and mutant tissues in vitro at 30 degrees C, the restrictive temperature. Both C and 25C were equally 7,8-dehydrogenated in situ to 7dC or 7d25C, respectively, by both wild type and mutant tissues at 30 degrees C. However, the rate of subsequent conversion of either of these delta 5,7-sterol intermediates synthesized in situ to ecdysteroids was reduced an average of 50% in the mutant tissues relative to the wild type. Yet, when emulsified 7d25C was incubated directly with either the wild type or mutant tissues at the restrictive temperature, the amplified rate of conversion of the freely available 7d25C to ecdysteroid by these tissues was identical. These data suggest that the defect in ecd1 tissue-mediated ecdysteroidogenesis does not involve a "hit" on any of the enzymes involved in either the 7,8-dehydrogenation of C or 25C or in the subsequent oxidation of 7d25C or 7dC to ecdysteroid. Rather, the mutation appears to affect the expression of a gene governing the translocation of delta 5,7-sterol intermediates from the subcellular compartment where they are synthesized and/or stored to the site of subsequent oxidation to ecdysteroid. |
| Differential influence of LDL cholesterol and triglycerides on lipoprotein(a) concentrations in diabetic patients Hernandez, C., P. Chacon, et al. (2001), Diabetes Care 24(2): 350-5. Abstract: OBJECTIVE: To evaluate the relationship between plasma lipid profiles and lipoprotein(a) Lp(a) concentrations in diabetic patients, taking into account the Lp(a) phenotype. RESEARCH DESIGN AND METHODS: We included 191 consecutive diabetic outpatients (69 type 1 and 122 type 2 diabetic patients) in a cross-sectional study Serum Lp(a) was determined by enzyme-linked immunosorbent assay, and Lp(a) phenotypes were assessed by SDS-PAGE followed by immunoblotting. The statistical methods included a stepwise multiple regression analysis using the Lp(a) serum concentration as the dependent variable. The lipid profile consisted of total cholesterol, HDL cholesterol, LDL cholesterol, corrected LDL cholesterol, triglycerides, and apolipoproteins AI and B. RESULTS: In the multiple regression analysis, LDL cholesterol (positively) and triglycerides (negatively) were independently related to the Lp(a) concentration, and they explained the 6.6 and 7.8% of the Lp(a) variation, respectively. After correcting LDL cholesterol, the two variables explained 3.8 and 6.4% of the Lp(a) variation, respectively. In addition, we observed that serum Lp(a) concentrations were significantly lower in patients with type IV hyperlipidemia (mean 1.0 mg/dl range 0.5-17, n = 16) than in normolipidemic patients (6.5 mg/dl 0.5-33.5, n = 117) and in type II hyperlipidemic patients (IIa 15.5 mg/dl 3.5-75, n = 13; IIb 9 mg/dl 1-80, n = 45); P < 0.001 by analysis of variance. CONCLUSIONS: Lp(a) concentrations were directly correlated with LDL cholesterol and negatively correlated with triglyceride levels in diabetic patients. Therefore, our results suggest that the treatment of diabetic dyslipemia may indirectly affect Lp(a) concentrations. |
| Differential inhibitory effects of garlic-derived organosulfur compounds on cholesterol biosynthesis in primary rat hepatocyte cultures Gebhardt, R. and H. Beck (1996), Lipids 31(12): 1269-76. Abstract: Using primary rat hepatocyte cultures, the potency of several garlic-derived organosulfur compounds to inhibit cholesterol biosynthesis in toto as well as at early and late steps of this metabolic pathway was compared. Concerning early steps, allicin significantly inhibited incorporation of 14Cacetate into nonsaponifiable neutral lipids already at concentrations as low as 10 microM, while diallyl disulfide and allyl mercaptan were effective above 100 microM only. Likewise, inhibition in response to the two vinyl-dithiins started at 500 microM. If 14Cacetate was replaced by 14Cmevalonate, inhibition due to allicin, diallyl disulfide, and allyl mercaptan disappeared suggesting that HMGCoA-reductase was the target of inhibition. In contrast, for the vinyl-dithiins a stimulation of mevalonate incorporation was found. Concerning the late step, the potency to exert accumulation of lanosterol presumably by inhibiting lanosterol 14 alpha-demethylase decreased in the order allicin > diallyl disulfide > allyl mercaptan = 1,3-vinyl-dithiin >> 1,2-vinyldithiin, the effect of the latter compound being close to zero. With respect to the total inhibition of 14Cacetate labeling of cholesterol, the half-maximal effective concentration-value of allicin was determined to be 17 +/- 2 microM compared to 64 +/- 7 microM for diallyl disulfide and to 450 +/- 20 microM for allyl mercaptan. Cytotoxicity as determined by the lactate dehydrogenase leakage assay was slightly higher for the two vinyl-dithiins than for diallyl disulfide and allyl mercaptan, but was apparent only at concentrations higher than 10 mM and, consequently, was irrelevant for the effects described. These results demonstrate that different garlic-derived organosulfur compounds interfere differently with cholesterol biosynthesis and, thus, may provoke multiple inhibition of this metabolic pathway in response to garlic consumption. The fact that allicin was the most effective inhibitor argues against the possibility that its degradation products, namely diallyl disulfide or allyl mercapatan, might mediate its effects, a possibility that might be true, however, in the case of the vinyl-dithiins. |
| Differential interaction of the two cholesterol-dependent, membrane-damaging toxins, streptolysin O and Vibrio cholerae cytolysin, with enantiomeric cholesterol Zitzer, A., E. J. Westover, et al. (2003), FEBS Lett 553(3): 229-31. Abstract: Membrane cholesterol is essential to the activity of at least two structurally unrelated families of bacterial pore-forming toxins, represented by streptolysin O (SLO) and Vibrio cholerae cytolysin (VCC), respectively. Here, we report that SLO and VCC differ sharply in their interaction with liposome membranes containing enantiomeric cholesterol (ent-cholesterol). VCC had very low activity with ent-cholesterol, which is in line with a stereospecific mode of interaction of this toxin with cholesterol. In contrast, SLO was only slightly less active with ent-cholesterol than with cholesterol, suggesting a rather limited degree of structural specificity in the toxin-cholesterol interaction. |