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At least 73 records · Page 4Linked to original sources
PubMed2000

Sterols and inhibitors of sterol transport modulate the degradation and secretion of macrophage ApoE: requirement for the C-terminal domain.

Macrophage-derived apoE, produced in the vessel wall, may have important effects during atherogenesis. The production of apoE by macrophages can be regulated at a transcriptional level by cellular differentiation state, cytokines and sterol loading. In addition, there are post-transcriptional and post-translational loci for regulation. We have recently identified an intermediate density cell membrane fraction in which the degradation of apoE can be modulated by sterols. Suppressing degradation of apoE in this fraction by pre-incubating cells in sterols led to enhanced apoE secretion. In this report we demonstrate that the suppressive effect of sterols on the degradation of newly synthesized apoE in this fraction depends on the presence on its C-terminal domain, by studying a macrophage cell line transfected to express a mutant form of apoE in which amino acids beyond amino acid 202 were deleted. In addition, two modulators of cellular sterol transport, progesterone and U1866A, inhibited the degradation of full-length apoE. In contrast, incubation of cells in the acyl-CoA:cholesterol acyltransferase inhibitor S58035 did not influence apoE degradation. As would be predicted based on the results of degradation assays, U1866A, but not S58035, increased the secretion of apoE from a cell line transfected to constitutively express full-length apoE cDNA. The effect of U1866A on apoE degradation, like the effect of sterol, required the presence of the apoE C-terminal domain. Our results indicate that alteration of intracellular sterol homeostasis by pre-incubation in sterols or by drugs that modify the subcellular transport of sterol, modulates the susceptibility of apoE to degradation and that this modulation requires the presence of C-terminal lipid binding domains.

Apolipoproteins E↗
PubMed2003

Enzymological properties of sterol-C4-methyl-oxidase of yeast sterol biosynthesis.

Despite genes of the sterol methyl-oxidase component (SMO) of the sterol-C4-demethylation multienzymatic complex have been identified in a variety of organisms and the key role played by SMO in yeast sterol biosynthesis, the enzymological properties of yeast SMO have not been investigated. An enzymatic assay for measuring specifically sterol 4alpha-methyl-oxidase activity in Saccharomyces cerevisiae has been developed for the first time by using [14C]-4,4-dimethyl-zymosterol as substrate. It allowed enzymatically formed C4 mono- and di-demethylated products to be characterized as well as two novel C4-hydroxymethyl-zymosterol derivatives to be identified as immediate oxidative metabolites by the yeast 4,4-dimethyl-zymosterol 4alpha-methyl-oxidase (ScSMO). The properties of microsomal ScSMO have been established with respect to cofactor requirements and kinetics and the substrate selectivity examined with a number of 4,4-dimethyl- and 4alpha-methyl-sterols. Remarkably, ScSMO showed very low activity with 24-methylene-24-dihydrocycloartenol, the natural substrate of maize 4,4-dimethyl-sterol-C4-methyl-oxidase. Conversely, maize sterol-C4-methyl-oxidases showed extremely reduced activity with the natural substrate of ScSMO. The previously described antifungal agent, 6-amino-2-n-pentylbenzothiazole was shown to directly inhibit the microsomal ScSMO activity in vitro. The yeast system was more than 500 times more sensitive to this derivative than the maize systems. These distinct substrate specificities and inhibitor sensitivities between yeast and plant sterol-4alpha-methyl-oxidases probably reflect diversity in the structure of their active sites in relation to the distinct sterol biosynthetic pathways.

Antifungal Agents↗
PubMed1981

Sterol metabolism in the rat: effect of alcohol on sterol metabolism in two strains of rats.

Sterol metabolism studies using a combination of isotopic and chromatographic procedures were carried out in two strains of rats fed 5% ethanol (36% of calories) in the diet. Feeding ethanol to the Fisher rat over 17 days produced no significant changes in body weight. Cholesterol levels in various tissues were elevated in the ethanol-fed group: plasma cholesterol, +61%; liver cholesterol, +47%; and bile cholesterol, +57%. The alcohol-fed Fisher rat showed several changes in sterol metabolism over controls: fecal acidic steroid output, +13%; fecal neutral sterol output, +51%; endogenous neutral sterol output, +107%; cholesterol turnover, +54%; and cholesterol balance, +18%. Ethanol feeding to the Sprague Dawley rat showed similar differences between ethanol-fed vs. control rats. Cholesterol levels were significantly elevated in plasma (+35%) and in the liver (+81%). Sterol metabolism data showed the following differences (alcohol vs. control): fecal acidic steroid output, +9%; fecal neutral sterol output, +17%; endogenous neutral sterol output, +72%; cholesterol turnover, +33%; and cholesterol balance +13%. The Fisher rat maintained almost constant weight throughout the experimental period and is a preferable strain for sterol balance studies using liquid diets. A major finding of these experiments was the increased concentration of cholesterol in liver, plasma, and bile in both strains of rats. The sterol balance measurements indicated that this tissue accumulation of cholesterol was due to enhanced cholesterol synthesis as well as inhibition of bile acid syntheses.

Animals↗
PubMed1993

Sterol composition of yeast organelle membranes and subcellular distribution of enzymes involved in sterol metabolism.

Organelles of the yeast Saccharomyces cerevisiae were isolated and analyzed for sterol composition and the activity of three enzymes involved in sterol metabolism. The plasma membrane and secretory vesicles, the fractions with the highest sterol contents, contain ergosterol as the major sterol. In other subcellular membranes, which exhibit lower sterol contents, intermediates of the sterol biosynthetic pathway were found at higher percentages. Lipid particles contain, in addition to ergosterol, large amounts of zymosterol, fecosterol, and episterol. These sterols are present esterified with long-chain fatty acids in this subcellular compartment, which also harbors practically all of the triacylglycerols present in the cell but very little phospholipids and proteins. Sterol delta 24-methyltransferase, an enzyme that catalyzes one of the late steps in sterol biosynthesis, was localized almost exclusively in lipid particles. Steryl ester formation is a microsomal process, whereas steryl ester hydrolysis occurs in the plasma membrane and in secretory vesicles. The fact that synthesis, storage, and hydrolysis of steryl esters occur in different subcellular compartments gives rise to the view that ergosteryl esters of lipid particles might serve as intermediates for the supply of ergosterol from internal membranes to the plasma membrane.

Esterases↗
PubMed2003

Differential effects of polyunsaturated fatty acids on sterol synthesis rates in adult and fetal tissues of the hamster: consequence of altered sterol balance.

Cholesterol is necessary for the proper growth and development of the fetus. Consequently, disruptions in cholesterol biosynthesis lead to abnormal fetal development. It has been shown that in cells exposed to polyunsaturated fatty acids (PUFA), the expressions of genes and activities of enzymes involved in cholesterol synthesis are reduced. Similarly, we found that adult male hamsters fed PUFA-enriched diets had an approximately 60% reduction in in vivo hepatic sterol synthesis rates. If fetal tissues respond to PUFA in the same manner as do adult livers, then maternal dietary PUFA could lead to a reduction in fetal sterol synthesis rates and possibly abnormal development. To investigate the impact of maternal dietary fatty acids on fetal sterol synthesis rates, female hamsters were fed diets enriched in various fatty acids before and throughout gestation. In vivo sterol synthesis rates were measured in fetuses at mid- and late gestation. At both gestational stages, dietary PUFA had no effect on fetal sterol synthesis rates. This lack of effect was not a consequence of a lack of PUFA enrichment in fetal fatty acids or the lack of PUFA receptor expression in the fetus. We hypothesize that the fetus may experience a dysregulation of sterol synthesis as the result of the fetus being in a negative sterol balance; the PUFA-induced suppression of sterol synthesis in the adult male hamster liver was ablated by creating a net negative sterol balance across the adult hepatocyte.

Animals↗
PubMed1998

Sterol-independent, sterol response element-dependent, regulation of low density lipoprotein receptor gene expression.

Stimulation with phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin increased native low density lipoprotein (LDL) receptor gene expression in the human leukemic T cell line Jurkat when cells were cultured in the absence of sterols and also increased nuclear accumulation of sterol regulatory element binding protein (SREBP)-1. PMA and ionomycin likewise increased LDL receptor mRNA levels when cells were cultured in the presence of suppressive concentrations of sterols, when neither SREBP-1 nor SREBP-2 was detectable in the nucleus. These findings indicated that mitogen-induced up-regulation of the LDL receptor gene could be independent of sterol-regulated transcription factors. The involvement of sterol regulatory element (SRE)-1 was analyzed by transfection of LDL receptor promoter constructs. Promoter fragments of either the 5' 1472 or 142 base pairs induced reporter gene expression after mitogenic stimulation when cells were cultured in the absence or presence of sterols. Mutation of the SRE-1 sequence in either construct abolished sterol-mediated regulation of transcription. However, mutation of the SRE-1 sequence in the 1472 base pair promoter fragment did not alter mitogenic induction of transcription, whereas mutation of SRE-1 in the 142 base pair promoter fragment completely prevented up-regulation of transcription. Taken together, these results demonstrate that the LDL receptor promoter contains at least one 5' SRE-independent as well as an SRE-dependent response element. Furthermore, the data suggest that the SRE-dependent response may not involve the action of either SREBP-1 or -2. Thus, mitogen-induced transcription of the LDL receptor promoter is regulated by diverse sterol-independent mechanisms.

Base Sequence↗
PubMed2004

Sterol transporters: targets of natural sterols and new lipid lowering drugs.

Recent insights in the role of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8, the discovery of ezetimibe, the first approved direct cholesterol absorption inhibitor, as well as the identification of Niemann-Pick C1 Like 1 (NPC1L1) protein as sterol transporter in the gut, focused attention on sterol transport processes in the small intestine and the liver. The identification of defective structures in the ABCG5 or ABCG8 transporters in patients with the rare disease of sitosterolemia elucidated their role as sterol efflux pumps regulating at least in parts the intestinal sterol absorption and the hepatic sterol output. ABCG5 and ABCG8 themselves are regulated by cholesterol via liver X receptors (LXRs), which are also activated by oxysterols and some derivatives of plant sterols. NPC1L1 could recently be identified as a major sterol transporter for the intestinal uptake of cholesterol as well as plant sterols. Studies in NPC1L1 knockout mice indicate that this transporter is essential for the intestinal uptake of sterols and that NPC1L1 might also be involved in the mechanism of action of ezetimibe. However, studies with photoreactive cholesterol as well as with photoreactive ezetimibe analogues suggest that other processes might also be involved in the mechanism of action of ezetimibe.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2000

Sterol-induced upregulation of phosphatidylcholine synthesis in cultured fibroblasts is affected by the double-bond position in the sterol tetracyclic ring structure.

We have examined how a specific enrichment of cultured fibroblasts with various sterols (cholesterol, lathosterol, 7-dehydrocholesterol, allocholesterol and dihydrocholesterol) regulate synthesis de novo of phosphatidylcholine, cholesterol and cholesteryl (or steryl) esters in human skin fibroblasts. When human skin fibroblasts were incubated for 1 h with 130 microM cholesterol/CyD complexes, the mass of cellular free cholesterol increased by 100 nmol.mg-1 protein (from 90 nmol.mg-1 to 190 nmol.mg-1 protein). A similar exposure of cells to different sterol/CyD complexes increased the cell sterol content between 38 and 181 nmol sterol per mg cell protein. In cholesterol-enriched cells, the rate of phosphatidylcholine synthesis was doubled compared to control cells, irrespective of the type of precursor used ([3H]choline, [3H]palmitic acid, or [14C]glycerol). Enrichment of fibroblasts with 7-dehydrocholesterol, allocholesterol, or dihydrocholesterol also upregulated phosphatidylcholine synthesis, whereas cells enriched with lathosterol failed to upregulate their phosphatidylcholine synthesis. The activity of membrane-bound CTP:phosphocholine cytidylyltransferase, the rate-limiting enzyme, was increased by 47 +/- 4% in cholesterol-enriched cells whereas its activity was unchanged in lathosterol-enriched cells. Sterol enrichment with all tested sterols (including lathosterol) down-regulated acetate-incorporation into cholesterol, and upregulated sterol esterification in the sterol-enriched fibroblasts. Using 31P-NMR to measure the lamellar-to-hexagonal (Lalpha-HII) phase transition in multilamellar lipid dispersions, lathosterol-containing membranes underwent their transition at significantly higher temperatures compared to membranes containing any of the other sterols. In a system with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine and either cholesterol or lathosterol (70:30 mol/mol), differential scanning calorimetry also revealed that the Lalpha-HII-transition occurred at a higher temperature with lathosterol compared to either cholesterol, allocholesterol, or dihydrocholesterol. These findings together suggest that there may exist a correlation between the propensity of a sterol to stabilize the Lalpha-HII-transition and its capacity to upregulate the activity of CTP:phosphocholine cytidylyltransferase in cells.

Cell Survival↗
PubMed2003

Red cell and plasma plant sterols are related during consumption of plant stanol and sterol ester spreads in children with hypercholesterolemia.

OBJECTIVE: To show whether the ratios of squalene and cholesterol precursor sterols to cholesterol and cholestanol and plant sterols to cholesterol change differently in plasma and especially in the red cells of hypercholesterolemic children during consumption of plant stanol and sterol ester spreads. STUDY DESIGN: In a randomized, double-blind, crossover study, hypercholesterolemic children (n = 23) consumed low-fat plant stanol and sterol ester spreads for 5-week periods separated by a 5-week washout period. Plasma and red cell lipids, squalene, and noncholesterol sterols were measured before and at the end of each period. RESULTS: The plant stanol and sterol ester spreads lowered plasma total (-9% and -6%, respectively) and low-density lipoprotein (-12% and -9%) cholesterol but had no effect on red cell cholesterol, high-density lipoprotein cholesterol, or plasma triglycerides. The ratios of plasma and red cell sitosterol and campesterol to cholesterol decreased by 32% to 36% (P <.001) with the plant stanol ester and increased by 40% to 52% (P <.001) with the sterol ester spread. CONCLUSIONS: Consumption of plant sterols increases and consumption of plant stanols decreases the ratios of plant sterols to cholesterol in red cells of hypercholesterolemic children proportionately to the respective changes in plasma.

Child↗
PubMed1980

Phytosterolaemia, xanthomatosis and premature atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis.

A fourth case is described in which phytosterolaemia, earlier diagnosed as familial hypercholesterolaemia, was associated with normocholesterolaemia, hypersplenism and premature atherosclerotic arterial disease requiring a three-vessel coronary bypass at the age of 29 years. During a follow-up of 5 years 22-26% and 27-30% of serum and bile sterols were plant sterols, respectively. In addition to campesterol and beta-sitosterol, stigmasterol and a fourth major plant sterol, tentatively identified as avenasterol, were found in bile, and in free and esterified forms in all serum lipoproteins. Analysis of faecal steroids and measurement of biliary lipid secretion indicated that in addition to enhanced absorption of plant sterols their decreased biliary secretion contributed to the development of phytosterolaemia. Impaired biliary cholesterol secretion was compensated for by a markedly reduced cholesterol but normal bile acid synthesis and resulted in bile undersaturated with respect to cholesterol, in a reduced intestinal cholesterol pool and in a very low faecal excretion of cholesterol as neutral sterols. Cholestyramine brought about a modest increase in cholesterol elimination as bile acids, increased cholesterol synthesis as evidenced by the sterol balance value and the increased cholesterol precursors squalene and methyl sterols in plasma and bile, and reduced the plasma cholesterol by 21% and plant sterols by 16%, but had no effect on the biliary composition of main sterols.

Absorption↗
PubMed2005

Upregulation of sterol C14-demethylase expression in Trypanosoma cruzi treated with sterol biosynthesis inhibitors.

Infection with the protozoan, Trypanosoma cruzi, is the cause of Chagas disease that occurs widely throughout Latin America. T. cruzi contains sterol biosynthesis enzymes, and produces sterol products similar to those found in fungi. Antifungal drugs that inhibit ergosterol biosynthesis have potent anti-T. cruzi activity in vitro and in animal models. In this report, we describe the effects of sterol biosynthesis inhibitors (simvistatin, zaragosic acid, terbinafine, a lanosterol synthase inhibitor, ketoconazole, and tridemorph) on the regulation of two sterol biosynthesis genes and their protein products. Culturing T. cruzi in the presence of the lanosterol synthase inhibitor, terbinafine, or ketoconazole increased mRNA levels of the sterol C14-demethylase gene approximately 7-12-fold. The sterol C14-demethylase protein levels were also elevated. The effects of the sterol biosynthesis inhibitors on hydroxymethylglutaryl-CoA reductase expression were minimal. Control of the upregulation of sterol C14-demethylase appears to be mediated through the 3'-untranslated region of the gene. The findings demonstrate that T. cruzi can specifically regulate gene expression in response to derangements in its cellular functions.

Animals↗
PubMed2002

Expression of a novel, sterol-insensitive form of sterol regulatory element binding protein 2 (SREBP2) in male germ cells suggests important cell- and stage-specific functions for SREBP targets during spermatogenesis.

Cholesterol biosynthesis in somatic cells is controlled at the transcriptional level by a homeostatic feedback pathway involving sterol regulatory element binding proteins (SREBPs). These basic helix-loop-helix (bHLH)-Zip proteins are synthesized as membrane-bound precursors, which are cleaved to form a soluble, transcriptionally active mature SREBP that regulates the promoters for genes involved in lipid synthesis. Homeostasis is conferred by sterol feedback inhibition of this maturation process. Previous work has demonstrated the expression of SREBP target genes in the male germ line, several of which are highly up-regulated during specific developmental stages. However, the role of SREBPs in the control of sterol regulatory element-containing promoters during spermatogenesis has been unclear. In particular, expression of several of these genes in male germ cells appears to be insensitive to sterols, contrary to SREBP-dependent gene regulation in somatic cells. Here, we have characterized a novel isoform of the transcription factor SREBP2, which is highly enriched in rat and mouse spermatogenic cells. This protein, SREBP2gc, is expressed in a stage-dependent fashion as a soluble, constitutively active transcription factor that is not subject to feedback control by sterols. These findings likely explain the apparent sterol-insensitive expression of lipid synthesis genes during spermatogenesis. Expression of a sterol-independent, constitutively active SREBP2gc in the male germ line may have arisen as a means to regulate SREBP target genes in specific developmental stages. This may reflect unique roles for cholesterol synthesis and other functional targets of SREBPs during spermatogenesis.

Amino Acid Sequence↗
PubMed2002

Co-ordinate regulation of sterol biosynthesis enzyme activity during accumulation of sterols in developing rape and tobacco seed.

The activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, sterol methyl transferase 1 and sterol acyltransferase, key enzymes involved in phytosterol biosynthesis were shown to be co-ordinately regulated during oilseed rape ( Brassica napus L.) and tobacco ( Nicotiana tabacum L.) seed development. In both plants, enzyme activities were low during the initial stages of seed development, increasing towards mid-maturation where they remained stable for a time, before declining rapidly as the oilseeds reached maturity. During seed development, the level of total sterols increased 12-fold in tobacco and 9-fold in rape, primarily due to an increase in steryl ester production. In both seed tissues, stages of maximum enzyme activity coincided with periods of high rates of sterol production, indicating developmental regulation of the enzymes to be responsible for the increases in the sterol content observed during seed development. Consistent with previous studies the data presented suggest that sterol biosynthesis is regulated by two key steps, although there may be others. The first is the regulation of carbon flux into the isoprenoid pathway to cycloartenol. The second is the flux from cycloartenol to Delta(5)-end-product sterols. The implications of the results in terms of enhancing seed sterol levels by genetic modification are also discussed.

Brassica napus↗
PubMed2005

Transport of newly synthesized sterol to the sterol-enriched plasma membrane occurs via nonvesicular equilibration.

The mechanism by which newly synthesized sterols are transported from their site of synthesis, the endoplasmic reticulum (ER), to the sterol-enriched plasma membrane (PM) is not fully understood. Studies in mammalian cells suggest that newly synthesized cholesterol is transported to the PM in Golgi-bypassing vesicles and/or via a nonvesicular process. Using the yeast Saccharomyces cerevisiae as a model system, we now rule out an essential role for known vesicular transport pathways in transporting the major yeast sterol, ergosterol, from its site of synthesis to the PM. We use a cyclodextrin-based sterol capture assay to show that transport of newly synthesized ergosterol to the PM is unaltered in cells defective in Sec18p, a protein required for almost all intracellular vesicular trafficking events; we also show that transport is not blocked in cells that are defective in formation of transport vesicles at the ER or in vesicle fusion with the PM. Our data suggest instead that transport occurs by equilibration (t(1/2) approximately 10-15 min) of ER and PM ergosterol pools via a bidirectional, nonvesicular process that is saturated in wild-type exponentially growing yeast. To reconcile an equilibration process with the high ergosterol concentration of the PM relative to ER, we note that a large fraction of PM ergosterol is found condensed with sphingolipids in membrane rafts that coexist with free sterol. We propose that the concentration of free sterol is similar in the PM and ER and that only free (nonraft) sterol molecules have access to a nonvesicular transport pathway that connects the two organelles. This is the first description of biosynthetic sterol transport in yeast.

Adenosine Triphosphatases↗
PubMed1968

Studies on the sterols and sterol esters of the intracellular organelles of maize shoots.

1. The composition of the esterified and unesterified sterols of the nuclear, chloroplastidic, mitochondrial and microsomal fractions of 21-day-old maize shoots was examined. 2. The microsomal and mitochondrial fractions contain the bulk of the sterols of the tissue. 3. Only 1% of the sterol isolated from all the organelles is esterified. 4. The nuclear fraction has the greatest proportion of esterified sterol and the microsomal fraction the least. 5. 4-Demethyl sterols constitute the bulk of both esterified and unesterified sterols in all organelle fractions. 6. Cholesterol is the major esterified 4-demethyl sterol of the nuclear and chloroplastidic fractions, but only the nuclear fraction has an appreciable proportion of unesterified cholesterol. 7. Sterol esters of linolenic acid are more abundant in the mitochondrial and microsomal fractions than in the other two fractions.

Cell Nucleus↗