| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| The serum LDL/HDL cholesterol ratio is influenced more favorably by exchanging saturated with unsaturated fat than by reducing saturated fat in the diet of women Muller, H., A. S. Lindman, et al. (2003), J Nutr 133(1): 78-83. Abstract: We compared the effects of a high fat diet 38.4% of energy (E%) from fat; HSAFA diet, polyunsaturated/saturated fatty acid (P/S) ratio = 0.14, a low fat diet (19.7 E% from fat; LSAFA diet, P/S = 0.17), both based on coconut oil, and a diet with a high content of mono- and polyunsaturated fatty acids (PUFA; 38.2 E% from fat; HUFA diet, P/S = 1.9) on serum lipoproteins. The 25 women studied consumed each diet for 3-wk periods in a crossover design. The two high fat diets were identical except for the quality of the test fat. The LSAFA diet was identical to the HSAFA diet except that half the fat was replaced by carbohydrates. Serum total cholesterol, LDL cholesterol and apoB concentrations did not differ between the HSAFA and the LSAFA diet periods. Total cholesterol, LDL cholesterol and apoB were lower when women consumed the HUFA diet than when they consumed the other two diets. HDL cholesterol and apoA-I were 15 and 11%, respectively, higher when women consumed the HSAFA diet than when they consumed the LSAFA diet; HDL cholesterol and apoA-I were lower when women consumed the HUFA diet than when they consumed the HSAFA diet, but not the LSAFA diet. The LDL cholesterol/HDL cholesterol and apoB/apoA-I ratios were higher when women consumed the LSAFA diet than when they consumed the HSAFA diet. The LDL/HDL cholesterol ratio was higher when women consumed either the LSAFA or the HSAFA diet than when they consumed the HUFA diet, whereas apoB/apoA-I was higher when women consumed the LSAFA diet than when they consumed the HUFA diet. Triacylglycerol and VLDL cholesterol were higher when women consumed the LSAFA diet than when they consumed either the HSAFA or the HUFA diet. We conclude that, to influence the LDL/HDL cholesterol ratio, changing the proportions of dietary fatty acids may be more important than restricting the percentage of total or saturated fat energy, at least when derived mainly from lauric and myristic acids, both of which increase HDL cholesterol. |
| The sex differences in cord-blood cholesterol and fatty-acid levels among Japanese fetuses Andoh, T., H. Uda, et al. (1997), J Epidemiol 7(4): 226-31. Abstract: We examined serum cholesterol and fatty-acid levels of cord blood and maternal blood samples collected from 193 Japanese fetuses and their mothers. Our study, which is the largest study of this kind ever conducted in Japan, is the first Japanese study reporting that total, high density lipoprotein (HDL) and non-HDL cholesterol levels in females were statistically significantly higher than those in males; the sex differences of total, HDL and non-HDL cholesterol levels were 8.5 mg/dl (P = 0.002), 4.5 mg/dl (P = 0.004) and 4.1 mg/dl (P = 0.045), respectively. The sex difference of total cholesterol was attributable to both HDL and non-HDL cholesterol. The sex of fetuses didn't show evident differences in cholesterol levels in maternal sera. Fatty-acid levels in cord blood were also higher in female fetuses than in male fetuses. However, none of the differences except for monoene fatty acids were statistically significant. Further investigations seem warranted to elucidate the mechanisms involved in our results. |
| The significance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis (review) Rao, K. N. (1995), Anticancer Res 15(2): 309-14. Abstract: Cholesterol is widely distributed in the animal kingdom and occurs in all cell membranes. Even though the majority of body cholesterol is synthesized by the liver and secreted as circulating lipoproteins, all cells in the body have genomic information for cholesterol biosynthesis. Cholesterol biosynthesis is under feedback regulation, and the cellular and circulating cholesterol levels are tightly regulated at several points, such as the rate limiting enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and farnesyl pyrophosphate synthetase and at the low density lipoprotein (LDL) receptor. The cholesterol content and the rate of cholesterol biosynthesis are elevated in proliferating normal tissues and tumors. Cholesterol biosynthesis happens much before DNA synthesis, and inhibiting cholesterol biosynthesis inhibits cell growth, suggesting a linkage between the cholesterol and DNA synthetic pathways. The exact nature of this linkage is not known. However, recent evidence that the farnesyl moiety in the cholesterol biosynthetic pathway is necessary for the activation of G-proteins, and of the ras oncoprotein P21 has provided a probable basis for understanding this linkage, through signal transduction pathways. Thus, farnesylation of G proteins and ras oncoprotein P21 underscores the importance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis. During normal cell growth and differentiation, LDL acts as a negative growth regulator and growth factors as positive signals, the neoplastic cell achieving autocrine growth due to the activation of protooncogens. It is interesting to note that in several types of cancer, the ras gene is mutated; these mutations could increase GTP binding, and lead to an activated p21. The activation of p21 would then be aided by continuous farnesylation due to stimulation of the cholesterol biosynthetic pathway in tumors. The cholesterol biosynthetic pathway, and ras p21 could therefore be used as targets for chemoprevention of cancer. |
| The size of lipid rafts: an atomic force microscopy study of ganglioside GM1 domains in sphingomyelin/DOPC/cholesterol membranes Yuan, C., J. Furlong, et al. (2002), Biophys J 82(5): 2526-35. Abstract: Atomic force microscopy has been used to study the distribution of ganglioside GM1 in model membranes composed of ternary lipid mixtures that mimic the composition of lipid rafts. The results demonstrate that addition of 1% GM1 to 1:1:1 sphingomyelin/dioleoylphosphatidylcholine/cholesterol monolayers leads to the formation of small ganglioside-rich microdomains (40-100 nm in size) that are localized preferentially in the more ordered sphingomyelin/cholesterol-rich phase. With 5% GM1 some GM1 microdomains are also detected in the dioleoylphosphatidylcholine-rich phase. A similar preferential localization of GM1 in the ordered phase is observed for bilayers with the same ternary lipid mixture in the upper leaflet. The small GM1-rich domains observed in these experiments are similar to the sizes for lipid rafts in natural membranes but considerably smaller than the ordered bilayer domains that have been shown to be enriched in GM1 in recent fluorescence microscopy studies of lipid bilayers. The combined data from a number of studies of model membranes indicate that lateral organization occurs on a variety of length scales and mimics many of the properties of natural membranes. |
| The Smith-Lemli-Opitz syndrome: a potentially fatal birth defect caused by a block in the last enzymatic step in cholesterol biosynthesis Tint, G. S., A. K. Batta, et al. (1997), Subcell Biochem 28: 117-44. |
| The sonic hedgehog receptor patched associates with caveolin-1 in cholesterol-rich microdomains of the plasma membrane Karpen, H. E., J. T. Bukowski, et al. (2001), J Biol Chem 276(22): 19503-11. Abstract: The Hedgehog signaling pathway is involved in early embryonic patterning as well as in cancer; however, little is known about the subcellular localization of the Hedgehog receptor complex of Patched and Smoothened. Since Hh has been found in lipid rafts in Drosophila, we hypothesized that Patched and Smoothened might also be found in these cholesterol-rich microdomains. In this study, we demonstrate that both Smoothened and Patched are in caveolin-1-enriched/raft microdomains. Immunoprecipitation studies show that Patched specifically interacts with caveolin-1, whereas Smoothened does not. Fractionation studies show that Patched and caveolin-1 can be co-isolated from buoyant density fractions that represent caveolae/raft microdomains and that Patched and caveolin-1 co-localize by confocal microscopy. Glutathione S-transferase fusion protein experiments show that the interaction between Patched and caveolin-1 involves the caveolin-1 scaffolding domain and a Patched consensus binding site. Immunocytochemistry data and fractionation studies also show that Patched seems to be required for transport of Smoothened to the membrane. Depletion of plasmalemmal cholesterol influences the distribution of the Hh receptor complex in the caveolin-enriched/raft microdomains. These data suggest that caveolin-1 may be integral for sequestering the Hh receptor complex in these caveolin-enriched microdomains, which act as a scaffold for the interactions with the Hh protein. |
| The source of cholesterol for progesterone synthesis in cultured preovulatory human granulosa cells Endresen, M. J., E. Haug, et al. (1990), Acta Endocrinol (Copenh) 123(3): 359-64. Abstract: There are three possible sources of cholesterol for immediate use in progesterone production by preovulatory human granulosa cells: follicular fluid high-density lipoprotein, de novo synthesis of cholesterol, and performed intracellular cholesteryl ester stores. In the present study these three alternatives were investigated. First, an in vitro model was established that mimics the preovulatory environment, including short-term cultures and use of autologous follicular fluid in the culture medium, instead of serum. Using this model it was found that the presence of high-density lipoprotein from follicular fluid in the culture medium did not affect the synthesis of progesterone by the granulosa cells. Next, addition of inhibitors of de novo sterol synthesis, like low-density lipoprotein, 25-OH cholesterol and compactin to the culture medium, did not reduce 14Cacetate incorporation into sterols and steroids by the cells. The sterol synthesis was accordingly interpreted to be at a low and therefore uninhibitable level. Finally, the content of free and esterified cholesterol in freshly isolated granulosa cells was found to be 50 +/- 7 and 52 +/- 13 pmol/mg cell protein, respectively. We suggest that neither follicular high-density lipoprotein nor endogenous synthesis is the immediate cholesterol source for the progesterone production in preovulatory human granulosa cells. However, granulosa cells have a large store of cholesteryl esters that may provide free cholesterol for the preovulatory progesterone production. |
| The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor Brown, M. S. and J. L. Goldstein (1997), Cell 89(3): 331-40. |
| The stability of the alkylating derivatives of oligodeoxyribonucleotides containing a cholesterol or phenazine radical added to the 3'-termination during their interaction with Acholeplasma laidlawii PG-8 Panchenko, L. P., O. V. Egorov, et al. (1991), Mikrobiol Zh 53(4): 58-63. Abstract: Stability of alkylating derivatives of decathymidylates protected on the 3'-terminal by cholesterol and phenazine residues has been studied in the process of their interaction with cells of Acholeplasma laidlawii PG-8. It is shown that the studied reagents are not split by nucleases of A. laidlawii PG-8 for the time necessary for alkylation of mycoplasma biopolymers. |
| The state of the heart. If you thought cholesterol was all you had to worry about, better think again Park, A. (2000), Time 156(22): 72-3. Abstract: As recently as five years ago, doctors thought they had a pretty clear picture of what causes a heart attack. They saw it as a plumbing problem: too much fat in the diet builds up in the blood vessels that feed the heart, creating stoppages that starve the heart of oxygen. It was an elegant model and one that patients could understand. But it's not that simple. Cholesterol, it turns out, is just the starting point of a cascade of interlocking events. Underlying the new research presented at the American Heart Association meeting last week was a clear message: this isn't your father's heart disease anymore. |
| The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking Zhang, J., N. Dudley-Rucker, et al. (2004), J Lipid Res 45(2): 223-31. Abstract: Recently, a new class of lipid-lowering agents has been described that upregulate LDL receptor (LDLr) activity. These agents are proposed to activate sterol-regulated gene expression through binding to the sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP). Here, we show that the steroidal LDLr upregulator, GW707, induces accumulation of lysosomal free cholesterol and inhibits LDL-stimulated cholesterol esterification, similar to that observed in U18666A-treated cells and in Niemann-Pick type C1 (NPC1) mutants. Moreover, we demonstrate that induction of the NPC-like phenotype by GW707 is independent of SCAP function. We find that treatment with GW707 does not increase SREBP-dependent gene expression above that observed in lipoprotein-starved cells. Rather, we show that the apparent increase in SREBP-dependent activity in GW707-treated cells is attributable to a failure to appropriately suppress sterol-regulated gene expression, as has been shown previously for U18666A-treated cells and NPC mutant fibroblasts. We further demonstrate that cells treated with either GW707 or U18666A fail to appropriately generate 27-hydroxycholesterol in response to LDL cholesterol. Taken together, these findings support a mechanism in which GW707 exerts its hypolipidemic effects through disruption of late endosomal/lysosomal sterol trafficking and subsequent stimulation of LDLr activity. |
| The steroidogenic acute regulatory protein (StAR): a window into the complexities of intracellular cholesterol trafficking Strauss, J. F., 3rd, C. B. Kallen, et al. (1999), Recent Prog Horm Res 54: 369-94; discussion 394-5. Abstract: Stimulation of steroid-producing cells of the gonads and adrenals with tropic hormone results in a marked increase in steroid hormone synthesis within minutes. The rate-limiting step in this acute steroidogenic response is the transport of cholesterol from the outer to the inner mitochondrial membrane, where the first committed step in steroid synthesis is performed by the side-chain cleavage enzyme system. This process of cholesterol translocation is blocked by inhibitors of protein synthesis, suggesting that the effect of trophic hormones, acting through the intermediacy of cAMP, most likely involves the de novo synthesis of a protein that is rapidly inactivated. The recently identified steroidogenic acute regulatory (StAR) protein appears to be the most likely candidate for the "labile" protein, based on the following observations: 1) Expression of StAR in COS-1 cells engineered to contain the cholesterol side-chain cleavage system substantially augments pregnenolone formation; 2) StAR protein is expressed almost exclusively in steroid-producing cells, except the trophoblast of the human placenta, and its presence is correlated with steroid hormone production; 3) StAR mRNA increases in response to cAMP; 4) StAR is a target for serine phosphorylation mediated by protein kinase A, a process that is essential for maximizing StAR activity; and 5) lack of functional StAR causes the autosomal recessive disease, congenital lipoid adrenal hyperplasia, characterized by markedly impaired gonadal and adrenal steroid hormone synthesis. Studies on the mechanism of action of StAR revealed that import into mitochondria is not essential to its steroidogenesis-enhancing activity and more likely represents a means of rapidly inactivating StAR. Truncation mutations and site-directed mutations established that the C-terminus of the StAR protein contains the functionally important domains. The demonstration of steroidogenic activity of recombinant StAR protein on isolated mitochondria from bovine corpus luteum using protein that lacks the mitochondrial targeting sequence confirmed that StAR import is not essential for its steroidogenic activity and suggested that StAR acts directly on the outer mitochondrial membrane in the absence of intermediary cytosolic factors. Evidence that StAR functions as a cholesterol transfer protein raises the possibility that StAR acts directly on lipids of the outer mitochondrial membrane, probably stimulating cholesterol desorption from the sterol-rich outer membrane and its movement to the relatively sterol-poor inner membrane. |
| The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein Alpy, F., M. E. Stoeckel, et al. (2001), J Biol Chem 276(6): 4261-9. Abstract: MLN64 is a transmembrane protein that shares homology with the cholesterol binding domain (START domain) of the steroidogenic acute regulatory protein. The steroidogenic acute regulatory protein is located in the inner membrane of mitochondria, where it facilitates cholesterol import into the mitochondria. Crystallographic analysis showed that the START domain of MLN64 is a cholesterol-binding domain. The present work was undertaken to determine which step of the intracellular cholesterol pathway MLN64 participates in. Using immunocytofluorescence, MLN64 colocalizes with LBPA, a lipid found specifically in late endosomes. Electron microscopy indicates that MLN64 is restricted to the limiting membrane of late endosomes. Microinjection or endocytosis of specific antibodies shows that the START domain of MLN64 is cytoplasmic. Deletion and mutagenesis experiments demonstrate that the amino-terminal part of MLN64 is responsible for its addressing. Although this domain does not contain conventional dileucine- or tyrosine-based targeting signals, we show that a dileucine motif (Leu(66)-Leu(67)) and a tyrosine residue (Tyr(89)) are critical for the targeting or the proper folding of the molecule. Finally, MLN64 colocalizes with cholesterol and Niemann Pick C1 protein in late endosomes. However, complementation assays show that MLN64 is not involved in the Niemann Pick C2 disease which, results in cholesterol lysosomal accumulation. Together, our results show that MLN64 plays a role at the surface of the late endosomes, where it might shuttle cholesterol from the limiting membrane to cytoplasmic acceptor(s). |
| The sterol-sensing domain of the Niemann-Pick C1 (NPC1) protein regulates trafficking of low density lipoprotein cholesterol Millard, E. E., S. E. Gale, et al. (2005), J Biol Chem 280(31): 28581-90. Abstract: The Niemann-Pick C1 (NPC1) protein is a key participant in intracellular sterol trafficking and regulation of cholesterol homeostasis. NPC1 contains a pentahelical region that is evolutionarily related to sterol-sensing domains found in other polytopic proteins involved in sterol interactions or sterol metabolism, including sterol regulatory element-binding protein cleavage-activating protein and hydroxymethylglutaryl-CoA reductase. To gain insight into the role of the sterol-sensing domain of NPC1, we examined the effect of point mutations in the NPC1 sterol-sensing domain on the trafficking of low density lipoprotein-derived cholesterol and sphingolipids. We show that an NPC1 P692S loss of function mutation results in decreased cholesterol delivery to the plasma membrane and endoplasmic reticulum. By contrast, NPC1 proteins carrying a L657F or D787N point mutation, which correspond to the activating SCAP L315F and D443N mutations, respectively, exhibit a gain of function phenotype. Specifically, cell lines expressing the NPC1 L657F or D787N mutations show a nearly 2-fold increase in the rates of low density lipoprotein cholesterol trafficking to the plasma membrane and to the endoplasmic reticulum, and more rapid suppression of sterol regulatory element-binding protein-dependent gene expression. Trafficking of sphingolipids is intact in the D787N and L657F cell lines. Our finding that D787N and L657F are activating NPC1 mutations provide evidence for a conserved mechanism for the sterol-sensing domain among cholesterol homeostatic proteins. |
| The stimulation of the cholesterol esterification pathway by atherogenic lipoproteins in macrophages Tabas, I. (1995), Curr Opin Lipidol 6(5): 260-8. Abstract: Cholesteryl-ester-loaded macrophages, or foam cells, are prominent features of atherosclerotic lesions and undoubtedly play important roles in lesion development. Foam cell formation involves the uptake of atherogenic lipoproteins or other cholesterol-rich particles by pathways that are down-regulated incompletely or not at all by cholesterol. In addition, postreceptor events that affect intracellular cholesterol metabolism play a critical role in foam cell formation. Increasing evidence shows that the ability of lipoproteins to stimulate cholesterol esterification is dependent upon a regulated and complex pathway that most likely involves one or more proteins in addition to the cholesterol esterifying enzyme itself. The molecular characterization of these proteins, as well as the study of intracellular cholesterol metabolism in vivo, represent important goals for our further understanding of foam cell biology and atherogenesis. |
| The structural mimicry of membrane sterols by tamoxifen: evidence from cholesterol coefficients and molecular-modelling for its action as a membrane anti-oxidant and an anti-cancer agent Wiseman, H., M. Cannon, et al. (1992), Biochim Biophys Acta 1138(3): 197-202. Abstract: The anti-cancer drug tamoxifen is a potent inhibitor of lipid peroxidation induced by Fe(III)-ascorbate in ox-brain phospholipid liposomes. Similar anti-oxidant effects, but with varying potencies, are also shown by 4-hydroxy-tamoxifen, cholesterol, ergosterol and 17-beta-oestradiol. We now describe a computer-graphic fitting technique that demonstrates a structural similarity between the five compounds. In addition, we have quantified the differences (relative to cholesterol) between the anti-oxidant activities of the compounds in terms of a novel expression referred to here as the cholesterol coefficient (Cc) Finally, we discuss how the inhibitory effect of tamoxifen on lipid peroxidation may result from a membrane stabilization that is associated with a decrease in membrane fluidity. This action may be related to the anti-proliferative effect exerted by tamoxifen on cancer and fungal cells. |
| The structural role of cholesterol in biological membranes Sugahara, M., M. Uragami, et al. (2001), J Am Chem Soc 123(32): 7939-40. |
| The structuring effects of amphotericin B on pure and ergosterol- or cholesterol-containing dipalmitoylphosphatidylcholine bilayers: a differential scanning calorimetry study Fournier, I., J. Barwicz, et al. (1998), Biochim Biophys Acta 1373(1): 76-86. Abstract: Amphotericin B (AmB) is the most widely used polyene antibiotic to treat systemic fungal infections which affect an increasing number of immunocompromised patients. It is generally thought that AmB forms pores within the fungi membranes by interacting with ergosterol, the main sterol of fungi. However, it also interacts with the cholesterol contained in mammalian cells, hence its toxicity. In order to have a better understanding of the interactions prevailing between AmB and sterols, differential scanning calorimetry was used to study various mixtures incorporating from 6.5 to 25 mol% of AmB in pure dipalmitoylphosphatidylcholine (DPPC) vesicles and in ergosterol- or cholesterol-containing DPPC vesicles. The sterol concentration was kept constant at 12.5 mol% with respect to the phospholipid. Our results show that three phases co-exist when AmB is dispersed in the pure phospholipid. One corresponds to the phospholipid phase alone. The two others are characterised by a broad transition at temperatures higher than the main transition temperature of the pure phospholipid, corresponding to the drug in interaction with the aliphatic chains of the lipid. The fact that the transition temperatures of these additional components are higher than that of the pure phospholipid suggests that AmB interacts strongly with the aliphatic chains of the lipid, consistent with the idea prevailing in the literature that AmB by itself may form pores in a lipid matrix. When AmB interacts with cholesterol-containing bilayers the thermograms also present three components. Upon increasing the concentration of AmB, though, an important broadening of these components is observed which is explained in terms of destabilisation of the organisation of the aliphatic chains. The situation is strikingly different if ergosterol is present in the lipid matrix. The thermograms remain unmodified as the concentration of AmB is increased and a broad transition, now involving only two components when the thermograms are decomposed, is observed. An analysis of the results shows that various interacting units, e.g. AmB+DPPC and (AmB+ergosterol)+DPPC, are present within the membrane. These units involve the phospholipid and hence contribute to its structurisation. The important differences between the thermograms obtained with the ergosterol- as compared to the cholesterol-containing bilayers, in spite of the structural similarity of these two sterols, provides strong evidence for the selectivity of interaction of AmB with ergosterol as compared to cholesterol. It is thus clear that the action of AmB on cholesterol- as compared to ergosterol-containing membranes results from different mechanisms. Finally, UV-visible spectra of AmB in pure as well as sterol-containing DPPC vesicles show the presence of absorption bands that give support to the interpretation derived from the calorimetric data. |
| The study of serum proteins and lipids with the aid of the quantity ultracentrifuge: VII. Some features of a system of lipoproteins which contain phospholipid but no free cholesterol. 1952 Turner, R. H., J. R. Snavely, et al. (2000), Yale J Biol Med 73(1-6): 273-86. |
| The study of the relationship between cholesterol and lipid concentration and suicidal behavior in patients with schizophrenia affective illness Rybakowski, J., J. Ainiyet, et al. (1996), Psychiatr Pol 30(5): 699-712. Abstract: In 143 patients (63 male, 80 female), admitted to the Department of Adult Psychiatry, University of Medical Sciences in Poznan, throughout the period from 1 October 95-31 March 96, with the diagnosis of schizophrenia (46 patients), endogenous depression (79 patients) or mania (18 patients), serum concentration of total cholesterol, LDL and HDL cholesterol, triglycerides and total lipids was estimated during the first days of admission. The occurrence of suicidal behaviors (thoughts, tendencies or acts) in these patients during the period of 3 months preceding the admission was also determined. The occurrence of suicidal behavior was found in 74 patients (30 male, 44 female). The persons revealing suicidal behaviors had significantly lower concentrations of total cholesterol, LDL cholesterol, triglycerides and total lipids compared with patients without such behaviors. This relationship was observed in all diagnostic groups as well as in both younger (below 32 years) and older (over 40 years) groups of patients. The results obtained confirm previous reports on the association between low cholesterol concentration and an increased risk of suicidal behavior in patients with psychiatric disorders. Authors discuss possible mechanisms and also clinical implications of this finding. |