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PubMed1981

Squalene epoxidase, oxido-squalene cyclase and cholesterol biosynthesis in normal and tumoral mucosa of the human gastro-intestinal tract. Evidence of post-HHG CoA regulation.

Cholesterol biosynthesis was evaluated in different parts of the human gastro-intestinal tract by incorporation of labelled acetic or mevalonic acid into non-saponifiable metabolites and also by measuring squalene epoxidase activity, oxido=squalene cyclase activity and dihydrolanosterol demethylation rate. With respect to rat liver, whole cholesterol biosynthesis was generally low and we found an anatomic localization of activity towards the end of the gastro-intestinal tract. The results of analysis of mevalonic acid metabolites implied the existence of post-HMG CoA regulation. A comparison with the corresponding dat obtained from homologous cancerous tissues (inthe case of high cholesterogenic activity) did not show a greater activity in the tumor, in spite of higher levels of epoxidase concentration.

Acetates↗
PubMed1969

Assay of the possible organization of particle-bound enzymes with squalene synthetase and squalene oxidocyclase systems.

Lanosterol was biosynthesized in pig liver homogenate from [4,8,12-(14)C(3)]farnesyl pyrophosphate and [4S-4-(3)H]NADPH through the intermediary formation of squalene labelled asymmetrically with (3)H. The biosynthetic lanosterol, freed from labelled 24,25-dihydrolanosterol, which was also synthesized, was converted into 24,25-dihydrolanosteryl acetate and subjected to chemical degradations to locate the position(s) of the (3)H label in the molecule. The ratio of (3)H at C-11 to that at C-12 was found to be 1.28. Although a certain inequality of labelling was thus indicated, experimental uncertainties did not permit the conclusion that the asymmetrically labelled squalene might have been cyclized preferentially from one end.

Animals↗
PubMed1986

A possible role for squalene in the pathogenesis of acne. II. In vivo study of squalene oxides in skin surface and intra-comedonal lipids of acne patients.

Skin surface lipids and lipids from open and closed comedones in acne patients were analysed by thin layer chromatography. The results showed that these lipids were enriched in polar lipids, as compared with the skin surface lipids obtained from controls without acne. In both open and closed comedones, these polar lipids appeared to be derived mainly from the oxidation of squalene, which is in agreement with our previous in vitro results. We suggest that squalene oxidation is the link between comedogenesis and bacterial colonization, and based on this, we propose a hypothesis of the pathogenesis of acne.

Acne Vulgaris↗
PubMed1997

Cloning and characterization of the Arabidopsis thaliana SQS1 gene encoding squalene synthase--involvement of the C-terminal region of the enzyme in the channeling of squalene through the sterol pathway.

Squalene synthase (SQS) catalyzes the first committed step of the sterol biosynthetic pathway. A full-length Arabidopsis thaliana SQS cDNA has been isolated by combining library screening and PCR-based approaches. Arabidopsis SQS is encoded by a small gene family of two genes (SQS1 and SQS2) which are organized in a tandem array. SQS1 and SQS2 have an identical organization with regard to intron positions and exon sizes and encode SQS isoforms showing a high level of sequence conservation (79% identity and 88% similarity). The isolated cDNA has been assigned to the SQS1 gene product, SQS1. RNA blot analysis has shown that the 1.6-kb SQS1 mRNA is detected in all plant tissues analyzed (inflorescenses, leaves, stems and roots) although the transcript is especially abundant in roots. Arabidopsis SQS1 isoform is unable to complement the SQS-defective Saccharomyces cerevisiae strain 5302, although SQS activity was detected in the microsomal fraction of the transformed yeast strain. However, a chimeric SQS resulting from the replacement of the 66 C-terminal residues of the Arabidopsis enzyme by the 111 C-terminal residues of the Schizosaccharomyces pombe enzyme was able to confer ergosterol prototrophy to strain 5302. Labeling studies using [3H]farnesyl-P2 and microsomal fractions obtained from yeast strains expressing either Arabidopsis SQS1 or chimeric Arabidopsis/S. pombe SQS derivatives indicated that the C-terminal region of the enzyme is involved in the channeling of squalene through the yeast sterol pathway.

Amino Acid Sequence↗
PubMed2004

Detection of antibodies to squalene: III. Naturally occurring antibodies to squalene in humans and mice.

An ELISA-based assay is described for the measurement of antibodies to squalene (SQE) in human serum and plasma. The assay was adapted from the previously described assay for murine antibodies to SQE (J. Immunol. Methods 267 (2002) 119). Like the murine SQE antibody assay, the human antibody assay used sterile cell culture 96-well plates coated with SQE (20 nmol/well). Phosphate-buffered saline (PBS)-0.5% casein was used as both a blocking agent and dilution buffer. The assay has a high through-put capacity and is reproducible and quantitative. This assay was used to evaluate samples from three different human cohorts. The first cohort was retired employees of the United States Army Medical Research Institute of Infectious Diseases (USAMRIID alumni). The mean age was 68 (N=40; range 58-82). Most were vaccinated with the U.S. licensed anthrax vaccine (AVA) and most had received several other vaccines through a USAMRIID special immunization program. The second cohort was of similar age (N=372; mean age 67; range 54-97) from the normal population of Frederick, MD and were not vaccinated with AVA. The third cohort (N=299) was from Camp Memorial Blood Center, United States Army Medical Department Activities, Fort Knox, KY. (No additional volunteer information is available.) Using this new ELISA method, antibodies to SQE were detected in all three of the cohorts. IgG antibodies to SQE were detected in 7.5% and 15.1% of the samples from the USAMRIID alumni and Frederick cohorts, respectively. These differences were not significantly different (chi((1))(2)=1.69, p=0.19). In contrast, no IgG antibodies to SQE were detected in the Fort Knox cohort which is significantly different than the Frederick cohort (chi((1))(2)=49.25, p<0.0001). IgM antibodies to SQE were detected in 37.5% and 32.3% of the samples from the USAMRIID and Frederick cohorts, respectively, but there was no significant difference between the cohorts. In the Fort Knox cohort, 19.4% of the samples were positive for IgM antibodies to SQE, which was significantly different from the Frederick cohort (chi((1))(2)=14.23, p=0.0002). Although the age of the volunteers from the Fort Knox cohort is unknown, the demographic of the donors at the blood bank volunteers is 85% 17-21 years of age. This suggested that the prevalence of antibodies to SQE may increase with age. This was confirmed with mouse studies in which the presence of antibodies was monitored as a function of time. No antibodies to SQE were detected in female BALB/c, B10.Br and C57BL/6 mice at 2 months of age, but they reached a maximum prevalence with 100% and 89% of animals testing positive for IgG and IgM antibodies to SQE, respectively, in the C57Bl/6 mice at 18 months of age. BALB/c and B10.Br mice also developed antibodies to SQE over time, but were at a lower prevalence than those observed in the C57BL/6 mice. Thirty-five of the 40 volunteers in the USAMRIID were vaccinated with AVA (mean no. doses=26; range 3-47). Comparison of the prevalence of antibodies to SQE from the AVA immunized group with the Frederick cohort revealed that there was no statistical differences for IgG (chi((1))(2)=2.3, p=0.13) or IgM (chi((1))(2)=0.33, p=0.56). When the data from the USAMRIID and Frederick cohorts were combined and analyzed for the presence of antibodies to SQE with respect to the sex of the volunteer, females (40.8%) were found to have a higher prevalence of IgM antibodies to SQE than men (28.4%) (chi((1))(2)=6.59, p=0.01). No significant difference was observed in the prevalence for IgG antibodies to SQE in females (17.7%) and males (12.5%). We conclude that antibodies to SQE occur naturally in humans; have an increased prevalence in females; are not correlated with vaccination with AVA; and appear to increase in prevalence with age.

Adjuvants, Immunologic↗
PubMed2000

Phenolic compounds and squalene in olive oils: the concentration and antioxidant potential of total phenols, simple phenols, secoiridoids, lignansand squalene.

The aim of this study was to evaluate the phenolic antioxidant and squalene content in a range of olive and seed oils. A mean of 290 +/- 38 (SEM) mg squalene/100 g was detected. However, while there was a weak significant difference between extra virgin (424 +/- 21 mg/kg) and refined virgin (340 +/- 31 mg/100 g; P<0.05) olive oils, highly significant differences were evident between extra virgin olive oils (P<0.0001) refined virgin olive oils (P<0.0001) and seed oils (24 +/- 5 mg/100 g). While seed oils were devoid, on average, the olive oils contained 196 +/- 19 mg/kg total phenolics as judged by HPLC analysis, but the value for extra virgin (232 +/- 15 mg/kg) was significantly higher than that of refined virgin olive oil (62 +/- 12 mg/kg; P<0.0001). Appreciable quantities of simple phenols (hydroxytyrosol and tyrosol) were detected in olive oils, with significant differences between extravirgin (41.87 +/- 6.17) and refined virgin olive oils (4.72 +/- 215; P<0.01). The major linked phenols were secoiridoids and lignans. Although extra virgin contained higher concentrations of secoiridoids (27.72 +/- 6.84) than refined olive oils (9.30 +/- 3.81) this difference was not significant. On the other hand, the concentration of lignans was significantly higher (P<0.001) in extra virgin (41.53 +/- 3.93) compared to refined virgin olive oils (7.29 +/- 2.56). All classes of phenolics were shown to be potent antioxidants. In future epidemiologic studies, both the nature and source of olive oil consumed should be differentiated in ascertaining cancer risk.

Antioxidants↗
PubMed2003

Squalene epoxidase as hypocholesterolemic drug target revisited.

Therapeutic success of statins has distinctly established inhibition of de novo hepatic cholesterol synthesis as an effective approach to lower plasma LDL-cholesterol, the major risk factor for atherosclerosis and coronary heart disease. Statins inhibit HMG CoA reductase, a rate limiting enzyme which catalyses conversion of HMG CoA to mevalonic acid. However, in this process statins also inhibit the synthesis of several non-sterols e.g. dolichols and ubiquinone, which are implicated in side effects observed with statins. This prompted many major pharmaceutical companies in 1990s to target selective cholesterol synthesis beyond farnesyl pyrophosphate. The enzymes squalene synthetase, squalene epoxidase and oxidosqualene cyclase were identified as potential targets. Though inhibitors of these enzymes have been developed, till date no compound has been reported to have entered clinical trials. We evaluated the literature to understand merits and demerits of pursuing squalene epoxidase as a target for hypocholesterolemic drug development. Squalene epoxidase catalyses the conversion of squalene to 2,3-oxidosqualene. Although it has been extensively exploited for antifungal drug development, it has received little attention as a target for hypocholesterolemic drug design. This enzyme though recognized in the early 1970s was cloned 25 years later. This enzyme is an attractive step for pharmacotherapeutic intervention as it is the secondary rate limiting enzyme and blocking cholesterol synthesis at this step may result in accumulation of only squalene which is known to be stable and non toxic. Synthesis of several potent, orally bioavailable inhibitors of squalene epoxidase has been reported from Yamonuchi, Pierre Fabre and Banyu pharmaceuticals. Preclinical studies with these inhibitors have clearly demonstrated the potential of squalene epoxidase inhibitors as hypocholesterolemic agents. Hypochloesterolemic therapy is intended for prolonged duration and safety is an important determinant in clinical success. Lack of clinical trials, despite demonstrated preclinical efficacy by oral route, prompted us to evaluate safety concerns with squalene epoxidase inhibitors. In dogs, NB-598, a potent competitive squalene epoxidase inhibitor has been reported to exhibit signs of dermatitis like toxicity which has been attributed by some reviewers to accumulation of squalene in skin cells. Tellurium, a non-competitive inhibitor of squalene epoxidase has been associated with neuropathy in weanling rats. On the other hand, increased plasma levels of squalene in animals and humans (such as occurring subsequent to dietary olive oil or squalene administration) are safe and associated with beneficial effect such as chemoprevention and hypocholesterolemic activity. In our view, high circulating levels of squalene epoxidase inhibitor may be responsible for dermatitis and neuropathy. Competitive inhibition and pharmacokinetic profile minimizing circulating plasma levels (e.g. by hepatic sequestration and high first pass metabolism) could be important determinants in circumventing safety concerns of squalene epoxidase inhibitors. Recently, cholesterol-lowering effect of green tea has been attributed to potent squalene epoxidase inhibition, which can be consumed in much higher doses without toxicological effect. These facts strengthen optimism for developing clinically safe squalene epoxidase inhibitors. Put in perspective squalene epoxidase appears to be undervalued target which merits attention for development of better hypocholesterolemic drugs.

Anticholesteremic Agents↗
PubMed1982

Metabolism of squalene in human fat cells. Demonstration of a two-pool system.

Human adipose tissue has been shown to contain exceptionally high concentrations of squalene. In the present experiments, it was shown that most of adipose tissue squalene is located in the fat cells. Of this squalene, 80% is located in the central neutral lipid droplet and 20% is bound to the microsomal membranes. Upon incubation of isolated fat cells with radiolabeled substrates, both the microsomal and the droplet squalene became labeled. The specific activity of microsomal squalene increased faster than that of droplet squalene. In addition, the microsomal squalene quickly equilibrated to a maximal specific activity, whereas the droplet squalene showed a steady increase in specific activity. These observations indicate rapid turnover of microsomal squalene and slow turnover of droplet squalene. Moreover, they reflect intracellular transfer of labeled squalene from microsomes to the lipid droplet. During a 3-hour incubation of fat cells with labeled substrates, 90% of the newly formed labeled squalene was transferred to the lipid droplet and only 10% was converted into cholesterol. The results demonstrate that adipocyte squalene can be segregated anatomically and functionally into two distinct pools: a small metabolically active pool in the microsomal membranes where squalene is synthesized and a large metabolically inactive pool in the fat droplet where squalene is stored. The intracellular transfer of de novo synthesized squalene into the fat droplet of fat cells is one mechanism of squalene accumulation in adipose tissue.

Acetates↗
PubMed1978

Plasma squalene: lipoprotein distribution and kinetic analysis.

Plasma squalene concentration is increased in hypertriglyceridemia. In 24 normotriglyceridemic and 12 hypertriglyceridemic subjects, whole plasma squalene correlated strongly with plasma triglyceride (r = 0.973, P < 0.001) in the latter. In normal postabsorptive plasma, squalene was found in each lipoprotein fraction, 50.8% in very low density lipoprotein, 25.6% in low density lipoprotein, and 23.6% in high density lipoprotein. When plasma triglyceride was increased by dietary intake in humans or by experimental diabetes in rats, plasma squalene increased correspondingly. Conversion of [(14)C]mevalonic acid into [(14)C]squalene and kinetic analysis of [(14)C]squalene die-away curves were studied in 17 subjects. Hypertriglyceridemia significantly increased the estimated metabolically active plasma squalene pool. This together with an increase in radioactivity of squalene (dpm/ml plasma) in hypertriglyceridemia suggested that squalene production was increased. Squalene specific activity curves in lipoprotein fractions from four chylomicronemic subjects demonstrated that each fraction had newly synthesized squalene and that total plasma squalene kinetics represent the composite of several individual die-away curves. We conclude that squalene in whole plasma and in lipoprotein fractions varies directly with triglyceride content. Hypertriglyceridemia expands the plasma pool of metabolically active squalene, and each lipoprotein fraction contains squalene that is metabolically active in cholesterol synthesis.

Adult↗
PubMed2000

Dietary squalene increases cholesterol synthesis measured with serum non-cholesterol sterols after a single oral dose in humans.

Studies considering long-term squalene consumption have revealed no consistent effects on serum cholesterol levels but the immediate effect of dietary squalene on cholesterol synthesis has not been studied. Thus, the effect of a single dose of dietary squalene on postprandial lipid metabolism was studied in 16 male volunteeers aged 22-79 years. Two oral fat meals a week apart were administered to every subject, one without (control) and the other with 500 mg of squalene. Lipids, retinyl palmitate, squalene and non-cholesterol sterols were measured at baseline and after 3, 4, 6, 9, 12 and 24 h postprandially in plasma, chylomicron, VLDL and VLDL bottom and, in six randomly chosen subjects, also in IDL, LDL and HDL. In the fasting samples, squalene was mainly transported in LDL and HDL, whereas in squalene-supplemented postprandium most of squalene was carried in the triglyceride-rich lipoproteins. Postprandial squalene and retinyl palmitate curves closely resembled each other. After the squalene-enriched dietary fat load, squalene was significantly increased compared to control fat loads in plasma, chylomicrons, VLDL and IDL. Squalene addition increased significantly lathosterol/campesterol ratio in chylomicrons and VLDL at 12 h and in VLDL bottom at 9-12 h, and increased significantly VLDL lanosterol/campesterol ratio at 12 h, indicating enhanced cholesterol synthesis caused by squalene. Plasma plant sterol levels remained unchanged. In conclusion, a single oral dose of squalene representing a potential daily dietary amount increases cholesterol synthesis within 9-12 h detected in chylomicrons, VLDL and VLDL bottom.

Administration, Oral↗
PubMed1992

Inhibition of cholesterol synthesis by cyclopropylamine derivatives of squalene in human hepatoblastoma cells in culture.

Two squalene derivatives, trisnorsqualene cyclopropylamine and trisnorsqualene N-methylcyclopropylamine, were synthesized and tested for inhibition of lanosterol and squalene epoxide formation from squalene in rat hepatic microsomes, and for the inhibition of cholesterol synthesis in human cultured hepatoblastoma (HepG2) cells. Trisnorsqualene cyclopropylamine inhibited [3H]-squalene conversion to [3H]squalene epoxide in microsomes (IC50 = 5.0 microM), indicating that this derivative inhibited squalene mono-oxygenase. Trisnorsqualene N-methylcyclopropylamine inhibited [3H]squalene conversion to [3H]lanosterol (IC50 = 12.0 microM) and caused [3H]-squalene epoxide to accumulate in microsomes, indicating that this derivative inhibited 2,3-oxidosqualene cyclase. Cholesterol biosynthesis from [14C]acetate in HepG2 cells was inhibited by both derivatives (IC50 = 1.0 microM for trisnorsqualene cyclopropylamine; IC50 = 0.5 microM for trisnorsqualene N-methylcyclopropylamine). Cells incubated with trisnorsqualene cyclopropylamine accumulated [14C]squalene, while cells incubated with trisnorsqualene N-methylcyclopropylamine accumulated [14C]squalene epoxide and [14C]squalene diepoxide. The concentration range of inhibitor which caused these intermediates to accumulate coincided with that which inhibited cholesterol synthesis. The results indicate that cyclopropylamine derivatives of squalene are effective inhibitors of cholesterol synthesis, and that substitutions at the nitrogen affect enzyme selectivity and thus the mechanism of action of the compounds.

Acetates↗
PubMed1994

Postabsorptive metabolism of dietary squalene.

Serum squalene, a non-steroid intermediate of cholesterol biosynthesis, originates mainly from endogenous cholesterol synthesis and partly from diet, especially in populations consuming a lot of olive oil rich in squalene. Its postabsorptive metabolism has not been studied in detail in humans. Its presence in chylomicrons and VLDL suggests that the removal of dietary squalene may reflect the metabolism of intestinal lipoproteins. Accordingly, we studied the postabsorptive metabolism of 1 g dietary squalene in 16 healthy subjects with apolipoprotein (apo) E 3/3 phenotype and in five type III hyperlipidemic apo E 2/2 homozygotes known to have a retarded chylomicron remnant removal, and compared the results with vitamin A fat load test. About 40% of the basal and 90% of the postabsorptive squalene was in lipoproteins < 1.019 g/ml. The peak concentrations of chylomicron squalene were at 6 h, and of triglyceride-rich nonchylo-fraction at 9-12 h in the controls. The peak values occurred later than those of vitamin A. At 24 h the levels still exceeded the basal ones. In type III dyslipoproteinemia, most of the basal and postabsorptive squalene was in lipoproteins of density less than 1.019 g/ml, the peak postabsorptive values occurred later than in the controls and the serum values remained above the control levels for up to 24 h. The squalene and vitamin A areas under the incremental response curves (AUC) were higher than in the control group. The AUCs of the two markers in chylomicron were correlated negatively and those in LDL+HDL were correlated positively with fasting HDL cholesterol levels, the respective correlations being opposite with fasting VLDL triglycerides. The postabsorptive profile of squalene levels resembled that of vitamin A in both groups, except that the squalene curves were shifted to a later time period. Thus, a delayed clearance of chylomicron remnants could be detected by analyzing serum squalene 6-24 h after the squalene-supplemented fat meal.

Adult↗
PubMed2000

Squalene: potential chemopreventive agent.

Squalene is a triterpene that is an intermediate of the cholesterol biosynthesis pathway and it can be obtained from the diet. Olive oil contains 0.2-0.7% squalene. The average intake of squalene is 30 mg/day in the United States, however, when consumption of olive oil is high, the intake of squalene can reach 200-400 mg/day as observed in Mediterranean countries. The decreased risk for various cancers associated with high olive oil consumption may be due to the presence of squalene. Experimental studies have shown that squalene can effectively inhibit chemically-induced colon, lung and skin tumourigenesis in rodents. The protective effect is observed when squalene is given before and/or during carcinogen treatment. The mechanisms involved for the chemopreventive activity of squalene may include inhibition of Ras farnesylation, modulation of carcinogen activation and anti-oxidative activities. However, several factors must be taken into consideration when the evidence for the inhibition of carcinogenesis by squalene is examined, these include the effective dose used and the time of exposure. The information obtained is from animal bioassays and the long-term effects from consuming increased levels of squalene are not known. Although animal studies have enhanced our understanding of the possible action of squalene in decreasing carcinogenesis, one must apply caution in extrapolating the information obtained in animal studies to humans, because of possible species differences. In order to evaluate the overall implications of squalene to human cancer prevention, further studies are needed to fully identify its protective effects, as well as possible detrimental effects.

Animals↗