FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2097042070> ?p ?o ?g. }

• W2097042070 endingPage "2798" @default.
• W2097042070 startingPage "2789" @default.
• W2097042070 abstract "Smith-Lemli-Opitz syndrome (SLOS) is an inherited autosomal recessive cholesterol deficiency disorder. Our studies have shown that in SLOS children, urinary mevalonate excretion is normal and reflects hepatic HMG-CoA reductase activity but not ultimate sterol synthesis. Hence, we hypothesized that in SLOS there may be increased diversion of mevalonate to nonsterol isoprenoid synthesis. To test our hypothesis, we measured urinary dolichol and ubiquinone, two nonsterol isoprenoids, in 16 children with SLOS and 15 controls, all fed a low-cholesterol diet. The urinary excretion of both dolichol (P < 0.002) and ubiquinone (P < 0.02) in SLOS children was 7-fold higher than in control children, whereas mevalonate excretion was comparable. In a subset of 12 SLOS children, a high-cholesterol diet decreased urinary mevalonate excretion by 61% (P < 0.001), dolichol by 70% (P < 0.001), and ubiquinone by 67% (P < 0.03). Our hypothesis that in SLOS children, normal urinary mevalonate excretion results from increased diversion of mevalonate into the production of nonsterol isoprenoids is supported. Dietary cholesterol supplementation reduced urinary mevalonate and nonsterol isoprenoid excretion but did not change the relative ratios of their excretion. Therefore, in SLOS, a secondary peripheral regulation of isoprenoid synthesis may be stimulated. Smith-Lemli-Opitz syndrome (SLOS) is an inherited autosomal recessive cholesterol deficiency disorder. Our studies have shown that in SLOS children, urinary mevalonate excretion is normal and reflects hepatic HMG-CoA reductase activity but not ultimate sterol synthesis. Hence, we hypothesized that in SLOS there may be increased diversion of mevalonate to nonsterol isoprenoid synthesis. To test our hypothesis, we measured urinary dolichol and ubiquinone, two nonsterol isoprenoids, in 16 children with SLOS and 15 controls, all fed a low-cholesterol diet. The urinary excretion of both dolichol (P < 0.002) and ubiquinone (P < 0.02) in SLOS children was 7-fold higher than in control children, whereas mevalonate excretion was comparable. In a subset of 12 SLOS children, a high-cholesterol diet decreased urinary mevalonate excretion by 61% (P < 0.001), dolichol by 70% (P < 0.001), and ubiquinone by 67% (P < 0.03). Our hypothesis that in SLOS children, normal urinary mevalonate excretion results from increased diversion of mevalonate into the production of nonsterol isoprenoids is supported. Dietary cholesterol supplementation reduced urinary mevalonate and nonsterol isoprenoid excretion but did not change the relative ratios of their excretion. Therefore, in SLOS, a secondary peripheral regulation of isoprenoid synthesis may be stimulated. Children with Smith-Lemli-Opitz syndrome (SLOS) have a defect in the cholesterol biosynthetic pathway at the step of sterol-Δ7-reductase (EC 1.3.1.21), which converts 7-dehydrocholesterol (7-DHC) to cholesterol, resulting in increased levels of 7-DHC and low levels of cholesterol in plasma and tissues (1Battaile K.P. Steiner R.D. Smith-Lemli-Opitz syndrome: the first malformation syndrome associated with defective cholesterol synthesis..Mol. Genet. Metab. 2000; 71: 154-162Crossref PubMed Scopus (45) Google Scholar, 2Kelley R.I. A new face for an old syndrome..Am. J. Med Genet. 1997; 68: 251-256Crossref PubMed Scopus (66) Google Scholar, 3Porter F.D. RSH/Smith-Lemli-Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis..Mol. Genet. Metab. 2000; 71: 163-174Crossref PubMed Scopus (86) Google Scholar). The clinical manifestations of this inherited autosomal recessive metabolic syndrome include severe growth deficiency and congenital malformations as well as endocrine and neurological dysfunction, including in most cases mental retardation (4Herman G.E. Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes..Hum. Mol. Genet. 2003; 12 (Spec. No. 1): R75-R88Crossref PubMed Google Scholar). It seems unlikely that such varied, multifaceted, and seemingly unrelated clinical abnormalities can be accounted for solely by a reduction in cholesterol and/or an accumulation of cholesterol precursors and their metabolites. In this study, we suggest other biochemical disturbances. HMG-CoA reductase is the key rate-limiting enzyme in the biosynthesis of cholesterol and its precursors. Intermediates of cholesterol biosynthesis serve as precursors for the synthesis of a number of biologically active molecules, which play a vital role in maintaining cellular integrity and function. Changes in the activity of HMG-CoA reductase normally reflect changes in the rates of whole body cholesterol synthesis and can be readily measured by determining the urinary concentrations of its product mevalonate, the precursor of both cholesterol and nonsterol isoprenoids (5Illingworth D.R. Pappu A.S. Gregg R.E. Increased urinary mevalonic acid excretion in patients with abetalipoproteinemia and homozygous hypobetalipoproteinemia..Atherosclerosis. 1989; 76: 21-27Abstract Full Text PDF PubMed Scopus (24) Google Scholar, 6Parker T.S. McNamara D.J. Brown C.D. Kolb R. Ahrens Jr., E.H. Alberts A.W. Tobert J. Chen J. De Schepper P.J. Plasma mevalonate as a measure of cholesterol synthesis in man..J. Clin. Invest. 1984; 74: 795-804Crossref PubMed Scopus (134) Google Scholar). Studies in our laboratory have shown that urinary mevalonate excretion in SLOS children maintained on a very low-cholesterol diet is comparable with that observed in control children given the same diet. Mevalonate excretion is subject to sustained reduction when dietary cholesterol is increased (7Pappu A.S. Steiner R.D. Connor S.L. Flavell D.P. Lin D.S. Hatcher L. Illingworth D.R. Connor W.E. Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion..J. Lipid Res. 2002; 43: 1661-1669Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Thus, children with SLOS, who have low cholesterol levels, exhibit normal baseline HMG-CoA reductase activity and normal feedback inhibition by dietary cholesterol. We questioned whether the distal block in sterol synthesis in SLOS would affect nonsterol isoprenoid synthesis from mevalonate. We hypothesized that the combination of cholesterol deficiency in SLOS with normal urinary mevalonate excretion may indicate increased diversion of mevalonate to nonsterol isoprenoid synthesis and/or the mevalonate shunt pathway (Fig. 1 ). The mevalonate shunt links the cholesterol biosynthetic pathway with mitochondrial acetyl-CoA metabolism through the intermediate 3-methyl-glutaconic acid (8Landau B.R. Brunengraber H. Shunt pathway of mevalonate metabolism..Methods Enzymol. 1985; 110: 100-114Crossref PubMed Google Scholar). This intermediate is excreted in the urine when mevalonate production is stimulated and excessive. The studies of Kelley and Kratz (9Kelley R.I. Kratz L. 3-Methylglutaconic acidemia in Smith-Lemli-Opitz syndrome..Pediatr. Res. 1995; 37: 671-674Crossref PubMed Scopus (38) Google Scholar) have shown that increased flux through the mevalonate shunt does occur in SLOS subjects, as they excrete significant quantities of 3-methyl-glutaconic acid. We investigated whether in addition to the increase in the mevalonate shunt pathway in SLOS, there may be an increase in nonsterol isoprenoid synthesis. Increased levels of biologically important isoprenoids could contribute to the SLOS phenotype. In this study, we selected two nonsterol isoprenoids for measurement, ubiquinone and dolichol. These compounds are synthesized and excreted in quantities allowing their accurate determination in urine and have vital cellular functions, which make them attractive candidates for playing a role in the clinical abnormalities in SLOS. Ubiquinone serves as a universal antioxidant and, being a key member of the electron transport chain, participates in generating ATP by oxidative phosphorylation (10Dallner G. Sindelar P.J. Regulation of ubiquinone metabolism..Free Radic. Biol. Med. 2000; 29: 285-294Crossref PubMed Scopus (166) Google Scholar, 11Turunen M. Olsson J. Dallner G. Metabolism and function of coenzyme Q..Biochim. Biophys. Acta. 2004; 1660: 171-199Crossref PubMed Scopus (808) Google Scholar). Dolichol increases cell membrane fluidity and permeability, participates in n-glycosylation of proteins essential for their transport and function, and is important in the synthesis of phosphatidylinositol anchors for membrane proteins (12Krag S.S. The importance of being dolichol..Biochem. Biophys. Res. Commun. 1998; 243: 1-5Crossref PubMed Scopus (56) Google Scholar). We have shown that plasma mevalonate exhibits diurnal variations (13Pappu A.S. Illingworth D.R. Diurnal variations in the plasma concentrations of mevalonic acid in patients with abetalipoproteinaemia..Eur. J. Clin. Invest. 1994; 24: 698-702Crossref PubMed Scopus (20) Google Scholar). The 24 h urinary excretion of mevalonate reflects integrated plasma concentrations and provides a more practical way of assessing the flux of intermediates through the cholesterol biosynthetic pathway than blood. We assumed that there might be similar diurnal variations in blood isoprenoids. Hence, we did not measure these compounds in blood. Furthermore, a majority of the SLOS subjects (9 of 16) were children younger than 5 years of age. We were measuring many other metabolites in blood and are limited in the amount of blood we can safely collect in these small children. To test our hypothesis, we measured ubiquinone and dolichol excretion in the urine of SLOS children versus controls. We also determined the effectiveness of a high-cholesterol diet in decreasing isoprenoid excretion in SLOS children. Studies were conducted in the General Clinical Research Center (GCRC) at Oregon Health & Science University. Informed consent was obtained from the parents of each participant, and the Oregon Health and Science University Institutional Review Board approved the protocol. Table 1 shows the sex, age, and body weight of the 16 SLOS subjects enrolled in the study, together with the same values for 15 matched controls. The table also shows the anatomical severity score and DHCR7 mutations of the SLOS subjects.TABLE 1Description of experimental subjectsNo.SLOS SubjectsControl SubjectsSexFeedingAgeBody WeightSeverity ScoreMutationsSexAgeBody Weightyearskgyearskg1MaleGastrostomy tube0.55.411A247VIVS8-1G>CFemale8.737.72MaleGastrostomy tube2.38.572W37XY143XMale12243MaleOral4.320.520R352WW151XFemale8.439.14FemaleOral3.1311.517F284LV326LFemale2.4105MaleOral4.416.451A>gR446QFemale3.215.36FemaleOral10.423.210R450LIVS8-1G>CMale7.921.77FemaleOral11.321.710R450LIVS8-1G>CFemale2.812.38MaleOral29.76P51SIVS8-1G>CFemale1758.69MaleGastrostomy tube1.99.730Y462HIVS8-1G>CFemale233810MaleGastrostomy tube13.629.217F302LL470QFemale2142.411FemaleGastrostomy tube8.725.411F302LL470QFemale206412MaleOral12.361.86C380YIVS8-1G>CMale3474.613FemaleOral1236.911A247VIVS8-1G>CMale5.522.314FemaleOral16.45R242CV466MMale5.118.215FemaleOral23.545.322R352WIVS8-1G>CMale82316FemaleOral310.910T154MIVS8-1G>CMean7.122.416.411.933.4SD6.316.116.39.219.7SLOS, Smith-Lemli-Opitz syndrome. The controls consisted of normal recruited volunteers. Some subjects with SLOS were fed by gastrostomy, whereas others took nourishment orally. All subjects were maintained on a very low-cholesterol diet (23.5 ± 19 mg/day). Open table in a new tab SLOS, Smith-Lemli-Opitz syndrome. The controls consisted of normal recruited volunteers. Some subjects with SLOS were fed by gastrostomy, whereas others took nourishment orally. All subjects were maintained on a very low-cholesterol diet (23.5 ± 19 mg/day). Sixteen children with SLOS and 15 healthy age- and sex-matched control subjects were initially fed a very low-cholesterol diet (23.5 ± 19 mg/day) for a period of 3–4 weeks to approximate a uniform steady state with respect to sterol homeostasis (Table 1). Of 16 children with SLOS (8 females, 8 males), 5 were fed by gastrostomy tube and the others took nourishment orally. Parents were given both oral and written dietary instructions by registered dietitians and were asked to maintain dietary intake records. Subjects were admitted to the GCRC for 1 week periods at each dietary phase (low and high cholesterol) to obtain precise dietary control and urine collections. Some of the control subjects were outpatients. The parents provided 3 day dietary records. All SLOS children receiving the very low-cholesterol diet exhibited low to low-normal plasma cholesterol levels and measurable levels of 7-DHC and its metabolites (8-dehydrocholesterol and cholestatriene 3β-ol) (Table 2 ). The mean plasma cholesterol level of the control subjects was 158 ± 23 mg/dl.TABLE 2Plasma sterol composition in patients with SLOS fed a very low-cholesterol dietPlasma Sterols mg/dlNo.TotalCholesterol7-DHC8-DHCCholestatriene 3β-ol7-DHC and Its Metabolites7-DHC and Its Metabolites7-DHC/Cholesterol Ratio% total sterols1116.388.313.212.92.128.224.20.15232.68.014.39.21.124.675.51.79356.531.612.110.32.424.843.90.384123.2121.10.61.50.02.11.70.005143.1142.00.20.50.10.80.60.006105.095.04.75.30.410.49.90.05795.084.35.05.30.510.811.40.068100.594.84.82.60.37.77.70.05973.656.09.47.11.217.724.00.171063.539.812.69.31.823.737.30.321171.849.511.98.81.622.331.10.2412132.5104.513.611.82.628.021.10.131390.778.15.25.81.612.613.90.0714103.084.79.38.30.718.317.80.111565.944.910.89.50.721.031.90.2416106.7101.62.32.50.35.14.80.02Mean92.576.58.16.91.116.122.30.24SD29.935.44.83.70.89.219.10.437-DHC, 7-dehydrocholesterol; 8-DHC, 8-dehydrocholesterol. Plasma sterol levels were determined by GC as described in Materials and Methods. 7-DHC and its metabolites include 7-DHC, 8-DHC, and cholestatriene 3β-ol. The mean plasma cholesterol level in control subjects was 158 ± 23 mg/dl. Open table in a new tab 7-DHC, 7-dehydrocholesterol; 8-DHC, 8-dehydrocholesterol. Plasma sterol levels were determined by GC as described in Materials and Methods. 7-DHC and its metabolites include 7-DHC, 8-DHC, and cholestatriene 3β-ol. The mean plasma cholesterol level in control subjects was 158 ± 23 mg/dl. All dietary studies were carried out precisely as described in our earlier studies (7Pappu A.S. Steiner R.D. Connor S.L. Flavell D.P. Lin D.S. Hatcher L. Illingworth D.R. Connor W.E. Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion..J. Lipid Res. 2002; 43: 1661-1669Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). The high-cholesterol diets consisted of the very low-cholesterol diet supplemented with hard-boiled egg yolk or crystalline cholesterol. A portion of the prepared food was analyzed as a measure of cholesterol intake. The cholesterol intake of study subjects fed the very low-cholesterol diet was 26 ± 24 mg/day, and that for subjects fed the high-cholesterol diet was 495 ± 212 mg/day. Twenty-four hour urine was collected using preweighed cotton diapers from infants and children with SLOS with physical limitations, according to the procedure reported previously (7Pappu A.S. Steiner R.D. Connor S.L. Flavell D.P. Lin D.S. Hatcher L. Illingworth D.R. Connor W.E. Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion..J. Lipid Res. 2002; 43: 1661-1669Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). From toilet-trained children, 24 h urine was collected. Urine from the diapers was extracted with a measured amount of distilled water. The total extract volume was calculated by adding urine weight and the volume of distilled water added for urine extraction. After noting the volume, aliquots of urine were taken for dolichol, ubiquinone, mevalonate, and creatinine measurements and stored at –20°C. The efficiency of extraction of mevalonate, dolichol, and ubiquinone from diaper was 99, 93, and 91%, respectively. Aliquots of urine were thawed and centrifuged at 2,000 g for 30 min at 4°C to remove insoluble residues. Mevalonic acid in the supernatant was phosphorylated using [32P]-γ-ATP (New England Nuclear) and purified pig liver mevalonate kinase. Mevalonate phosphate was extracted with ethanol and quantified using a modification of the isotope dilution chromatography method of Popjak et al. (14Popjak G. Boehm G. Parker T.S. Edmond J. Edwards P.A. Fogelman A.M. Determination of mevalonate in blood plasma in man and rat. Mevalonate “tolerance” tests in man..J. Lipid Res. 1979; 20: 716-728Abstract Full Text PDF PubMed Google Scholar). The coefficient of variation within experiment and between experiments was <5%. The presence of minute amounts of stool in the urine did not interfere with mevalonate estimations. Urinary mevalonate excretion in a given individual may vary by 35% under stable metabolic conditions (15Pappu A.S. Illingworth D.R. Bacon S. Reduction in plasma low-density lipoprotein cholesterol and urinary mevalonic acid by lovastatin in patients with heterozygous familial hypercholesterolemia..Metabolism. 1989; 38: 542-549Abstract Full Text PDF PubMed Scopus (43) Google Scholar). Hence, we measured mevalonate in 24 h urine samples collected for 5 consecutive days of each dietary period. Mevalonate values are expressed as ng excreted/mg creatinine. Each urinary mevalonate value reported is the mean of mevalonate measurements from five independent determinations for each individual patient. Urinary dolichol was extracted and measured by reverse-phase HPLC. Dolichol was extracted from urine using Waters Sep-Pak® Vac Rc (500 mg) C18 cartridges using a modified procedure (16Kazunaga H. Suwaki H. Fuke C. Ameno K. Ijiri I. A study of urinary dolichols as a biological marker for alcohol abuse. Report I. Quantitation of urinary dolichols by high performance liquid chromatography after BondElutC18 (500 mg) cartridge extraction..Arukoru Kenkyuto Yakubutsu Ison. 1994; 29: 161-167PubMed Google Scholar). Fifteen to 40 ml of urine was applied to a Sep-Pak C18 column, which was previously washed with 8 ml of ethanol-methanol-2-propanol (90:5:5, v/v) and equilibrated with 8 ml of methanol and 8 ml of water. After washing the column with 8 ml of water and 8 ml of methanol, the dolichol was eluted with 8 ml of ethanol-methanol-2-propanol (90:5:5, v/v) and dried under N2, and the residue was dissolved in 100 μl of 2-propanol-methanol (72:28, v/v). Analytical recovery was determined by spiking urine samples with a known amount of dolichol-23 (Larodan AB, Malmo, Sweden). The recovery from extraction from the column was ∼85%. Separation of dolichol was performed using the HPLC system from the Waters 717 plus autosampler with the Waters 2487 dual absorbance detector (17Turpeinen U. Liquid-chromatographic determination of dolichols in urine..Clin. Chem. 1986; 32: 2026-2029Crossref PubMed Scopus (13) Google Scholar). The sample was injected onto a reverse-phase Phenomenex Luna 3u (C18) column (150 × 4.6 mm) and eluted with the mobile phase 2-propanol-methanol (72:28, v/v) at a flow rate of 0.8 ml/min, and the elute was monitored at a wavelength of 210 nm. The intra-assay and interassay variations were <8%. Urinary dolichol values for a given individual may vary by 23% under stable metabolic conditions. Hence, we measured dolichol levels in 24 h urine samples collected for 3 consecutive days of each dietary period. Therefore, each dolichol value is the average of three independent determinations. Urinary dolichol is expressed as ng excreted/mg creatinine. Ubiquinone from urine was extracted and measured by HPLC as described by Okamoto et al. (18Okamoto T. Fukui K. Nakamoto M. Kishi T. Okishio T. Yamagami T. Kanamori N. Kishi H. Hiraoka E. High-performance liquid chromatography of coenzyme Q-related compounds and its application to biological materials..J. Chromatogr. 1985; 342: 35-38Crossref PubMed Scopus (56) Google Scholar). Five milliliters of urine with 10 ml of methanol was extracted with 20 ml of hexane. After vigorous shaking, the hexane layer was collected and washed twice with 5 ml of distilled water and dried under N2. For dilute urine extracted from diapers, two to three 5 ml aliquots were processed and combined. The residue was dissolved in 100 μl of ethanol with 1 μg butylated hydroxytoluene/ml and subjected to HPLC. Ubiquinone was quantified using a Phenomenex Luna 3u (C18) column with a mobile phase of methanol-hexane (72:28, v/v) and detected at a wavelength of 275 nm. The intra-assay and interassay variations were <5%. Urinary ubiquinone values for a given individual may vary by 18% under stable metabolic conditions. Hence, we measured ubiquinone levels in 24 h urine samples collected for 3 consecutive days of each dietary period. Therefore, each ubiquinone value is the average of three independent determinations. Urinary ubiquinone is expressed as ng excreted/mg creatinine. For urinary creatinine, the GCRC Core Laboratory determined creatinine concentrations in the urine samples. For plasma sterols, venous blood samples were collected in EDTA-containing tubes from each individual when they were admitted to the GCRC. Plasma was separated by centrifugation of collected blood, and sterols were extracted from plasma, saponified with alcoholic KOH, and then converted to trisilyl derivatives, which were quantified by gas chromatography as described previously (19Steiner R.D. Linck L.M. Flavell D.P. Lin D.S. Connor W.E. Sterol balance in the Smith-Lemli-Opitz syndrome. Reduction in whole body cholesterol synthesis and normal bile acid production..J. Lipid Res. 2000; 41: 1437-1447Abstract Full Text Full Text PDF PubMed Google Scholar). Statistical analysis was performed using Student's t-test, paired t-tests, and ANOVA using SPSS software package 10.00 (SPSS, Inc.). Results are expressed as means ± SD. The urinary excretion of dolichol, ubiquinone, and mevalonate in children with SLOS and controls is summarized in Figs. 2 , 3 . The individual values of all subjects are given in Fig. 2, and the mean of each group is given in Fig. 3. With a very low-cholesterol diet, urinary mevalonate excretion in the SLOS subjects was similar to that in control subjects (760 ± 970 and 600 ± 810 ng/mg creatinine, SLOS vs. control). These results are in agreement with our earlier reported studies indicating that HMG-CoA reductase activity in children with SLOS is unaltered despite a reduction in plasma and cellular cholesterol (7Pappu A.S. Steiner R.D. Connor S.L. Flavell D.P. Lin D.S. Hatcher L. Illingworth D.R. Connor W.E. Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion..J. Lipid Res. 2002; 43: 1661-1669Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar).Fig. 3.Average values of urinary excretion of mevalonate (A), ubiquinone (B), and dolichol (C) in SLOS children (n = 16) and control children (n = 15) maintained on a very low-cholesterol diet. Urinary mevalonate is expressed as ng/mg creatinine and is an average of five independent determinations for each individual. Urinary dolichol and ubiquinone are expressed as ng/mg creatinine and are averages of three independent measurements. Values shown are means ± SD. * Significantly different from the corresponding value of control subjects (P < 0.02); ** significantly different from the corresponding value of control subjects (P < 0.002).View Large Image Figure ViewerDownload Hi-res image Download (PPT) In control subjects, the urinary excretion of ubiquinone varied from 12.8 to 370 (mean, 87.5 ± 87.8) ng/mg creatinine. In our control subjects, ubiquinone excretion was slightly above the range reported by Okamoto et al. (18Okamoto T. Fukui K. Nakamoto M. Kishi T. Okishio T. Yamagami T. Kanamori N. Kishi H. Hiraoka E. High-performance liquid chromatography of coenzyme Q-related compounds and its application to biological materials..J. Chromatogr. 1985; 342: 35-38Crossref PubMed Scopus (56) Google Scholar), 20–85 μg/g creatinine for adults. As the average age in our control subjects was 12.3 years, the higher levels seen in our studies compared with adult controls from the literature likely are a reflection of the measurement of ubiquinone in children versus adults. In SLOS subjects, the urinary ubiquinone excretion also varied widely from 24 to 3,320 (mean, 618 ± 857) ng/mg creatinine. However, the average ubiquinone excretion in SLOS subjects was significantly higher than that observed in control subjects (P < 0.02). One control subject, No. 7, had a very high urinary ubiquinone value of 370 ng/mg creatinine; however, this was significantly lower than that of her affected sibling, No. 14, with a value of 1,714 ng/mg creatinine. These subjects illustrate the wide variability that exists in urinary excretion of ubiquinone. Thus, ubiquinone excretion seems to vary widely in both SLOS and control children. In control subjects, urinary dolichol concentrations varied between 5.6 and 62.2 (mean, 31.5 ± 17.6) ng/mg creatinine. The values observed in our control subjects are comparable to previously published values for dolichol excretion, 23–106 μg/g creatinine (17Turpeinen U. Liquid-chromatographic determination of dolichols in urine..Clin. Chem. 1986; 32: 2026-2029Crossref PubMed Scopus (13) Google Scholar). Twenty-four hour dolichol excretion in SLOS subjects varied from 12 to 938 (mean, 213 ± 298) ng/mg creatinine. Urinary dolichol excretion in SLOS subjects was significantly higher than that observed in control subjects (P < 0.002). Our subjects exhibited wide variation in the excretion of nonsterol isoprenoids, especially ubiquinone, which may be attributable to the wide variation in age (20Miles M.V. Horn P.S. Tang P.H. Morrison J.A. Miles L. DeGrauw T. Pesce A.J. Age-related changes in plasma coenzyme Q10 concentrations and redox state in apparently healthy children and adults..Clin. Chim. Acta. 2004; 347: 139-144Crossref PubMed Scopus (82) Google Scholar, 21Pallottini V. Marino M. Cavallini G. Bergamini E. Trentalance A. Age-related changes of isoprenoid biosynthesis in rat liver and brain..Biogerontology. 2003; 4: 371-378Crossref PubMed Scopus (23) Google Scholar, 22Keller R.K. Nellis S.W. Quantitation of dolichyl phosphate and dolichol in major organs of the rat as a function of age..Lipids. 1986; 21: 353-355Crossref PubMed Scopus (28) Google Scholar, 23Elmberger G. Engfeldt P. Distribution of dolichol in human and rabbit blood..Acta Chem. Scand. B. 1985; 39: 323-325Crossref PubMed Scopus (22) Google Scholar). In SLOS children, a significant negative correlation was found between age and ubiquinone excretion (r = −0.75, P < 0.001). However, the correlation between age and dolichol excretion was not significant (r = −0.308, P < 0.25). Yet, when the subjects from the two groups were combined, a significant negative correlation was found between the age and both urinary ubiquinone excretion (r = −0.473, P < 0.017) and urinary dolichol excretion (r = −0.042, P < 0.035). There were no correlations between urinary excretion of nonsterol isoprenoids and plasma 7-DHC or 7-DHC/cholesterol ratio. There was no correlation between anatomical severity score and urinary excretion of mevalonate, ubiquinone, and dolichol. With regard to the DHCR7 mutation, our subjects are heterogeneous, making it difficult to appreciate any possible correlations between the mutation and nonsterol isoprenoid excretion. The SLOS children fed by gastrostomy tube were smaller in size and body weight and had significantly lower plasma cholesterol levels and high 7-DHC plus metabolites and high 7-DHC/cholesterol ratios compared with orally fed SLOS children. However, there were no significant differences between the two groups of SLOS children with regard to urinary mevalonate and nonsterol isoprenoid excretion. A subset of subjects with SLOS (n = 12) was fed a very low-cholesterol diet for 3–4 weeks and then a high-cholesterol diet for an average of 1.9 ± 1.2 years (Table 3 ). Our earlier studies have shown that one of the main desired effect in SLOS subjects, namely the reduction of plasma 7-DHC levels, occurred in most subjects only when maintained on a high-cholesterol diet for almost 24 months (7Pappu A.S. Steiner R.D. Connor S.L. Flavell D.P. Lin D.S. Hatcher L. Illingworth D.R. Connor W.E. Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion..J. Lipid Res. 2002; 43: 1661-1669Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Hence, we wanted to measure urinary isoprenoids in our subjects over a similar period of intervention. Furthermore, only one subject was local, and many others traveled from great distances to our site. We had to plan our studies according to the convenience of the families to accommodate their travel and availability, as they had to stay in the GCRC for 1 week periods.TABLE 3Effect of dietary cholesterol on plasma sterols in patients with SLOSPlasma SterolsType of DietValueDietary CholesterolBody WeightTotalCholesterol7-DHC8-DHCCholestatriene 3β-ola-7-DHC and Its Metabolites7-DHC/Cholesterol Ratiomg/daykgmg/dlVery low-cholesterol dietMean26.1024.2295.4579.837.846.871.1915.800.12SD23.8016.9722.9326.364.573.690.808.890.10High-cholesterol dietMean494.6130.03121.73107.437.216.260.8514.310.09SD212.4021.6931.5938.394.463.270.698.280.08P0.0000.0010.0000.9700.8500.3900.4700.009The children we" @default.
• W2097042070 created "2016-06-24" @default.
• W2097042070 creator A5002316792 @default.
• W2097042070 creator A5009712941 @default.
• W2097042070 creator A5010372404 @default.
• W2097042070 creator A5041452145 @default.
• W2097042070 creator A5051958225 @default.
• W2097042070 creator A5078703362 @default.
• W2097042070 creator A5084577141 @default.
• W2097042070 date "2006-12-01" @default.
• W2097042070 modified "2023-10-16" @default.
• W2097042070 title "Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol" @default.
• W2097042070 cites W1435404663 @default.
• W2097042070 cites W1481351448 @default.
• W2097042070 cites W1486489467 @default.
• W2097042070 cites W1550810733 @default.
• W2097042070 cites W1593369110 @default.
• W2097042070 cites W1876824915 @default.
• W2097042070 cites W1908899750 @default.
• W2097042070 cites W1941757869 @default.
• W2097042070 cites W1971101933 @default.
• W2097042070 cites W1971714188 @default.
• W2097042070 cites W1974095097 @default.
• W2097042070 cites W1975031336 @default.
• W2097042070 cites W1976728820 @default.
• W2097042070 cites W1980465185 @default.
• W2097042070 cites W1994048921 @default.
• W2097042070 cites W1994946347 @default.
• W2097042070 cites W1996473848 @default.
• W2097042070 cites W1996762890 @default.
• W2097042070 cites W1997722470 @default.
• W2097042070 cites W2000352166 @default.
• W2097042070 cites W2005841823 @default.
• W2097042070 cites W2006483680 @default.
• W2097042070 cites W2010028742 @default.
• W2097042070 cites W2029820638 @default.
• W2097042070 cites W2032637827 @default.
• W2097042070 cites W2036144176 @default.
• W2097042070 cites W2037465679 @default.
• W2097042070 cites W2040665626 @default.
• W2097042070 cites W2041442797 @default.
• W2097042070 cites W2045408341 @default.
• W2097042070 cites W2055281491 @default.
• W2097042070 cites W2071503492 @default.
• W2097042070 cites W2071820285 @default.
• W2097042070 cites W2073010850 @default.
• W2097042070 cites W2075994647 @default.
• W2097042070 cites W2084488493 @default.
• W2097042070 cites W2097803027 @default.
• W2097042070 cites W2100680747 @default.
• W2097042070 cites W2119315359 @default.
• W2097042070 cites W2121674642 @default.
• W2097042070 cites W2122713684 @default.
• W2097042070 cites W2129617240 @default.
• W2097042070 cites W2131808281 @default.
• W2097042070 cites W2156107893 @default.
• W2097042070 cites W2161257976 @default.
• W2097042070 cites W2170435243 @default.
• W2097042070 cites W2342546251 @default.
• W2097042070 cites W2614871251 @default.
• W2097042070 cites W4235797558 @default.
• W2097042070 doi "https://doi.org/10.1194/jlr.m600295-jlr200" @default.
• W2097042070 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16983147" @default.
• W2097042070 hasPublicationYear "2006" @default.
• W2097042070 type Work @default.
• W2097042070 sameAs 2097042070 @default.
• W2097042070 citedByCount "11" @default.
• W2097042070 countsByYear W20970420702012 @default.
• W2097042070 countsByYear W20970420702013 @default.
• W2097042070 countsByYear W20970420702014 @default.
• W2097042070 crossrefType "journal-article" @default.
• W2097042070 hasAuthorship W2097042070A5002316792 @default.
• W2097042070 hasAuthorship W2097042070A5009712941 @default.
• W2097042070 hasAuthorship W2097042070A5010372404 @default.
• W2097042070 hasAuthorship W2097042070A5041452145 @default.
• W2097042070 hasAuthorship W2097042070A5051958225 @default.
• W2097042070 hasAuthorship W2097042070A5078703362 @default.
• W2097042070 hasAuthorship W2097042070A5084577141 @default.
• W2097042070 hasBestOaLocation W20970420701 @default.
• W2097042070 hasConcept C104788683 @default.
• W2097042070 hasConcept C126322002 @default.
• W2097042070 hasConcept C134018914 @default.
• W2097042070 hasConcept C134651460 @default.
• W2097042070 hasConcept C181199279 @default.
• W2097042070 hasConcept C185592680 @default.
• W2097042070 hasConcept C206103511 @default.
• W2097042070 hasConcept C2778163477 @default.
• W2097042070 hasConcept C2780716534 @default.
• W2097042070 hasConcept C2781446604 @default.
• W2097042070 hasConcept C553450214 @default.
• W2097042070 hasConcept C55493867 @default.
• W2097042070 hasConcept C71924100 @default.
• W2097042070 hasConcept C86803240 @default.
• W2097042070 hasConceptScore W2097042070C104788683 @default.
• W2097042070 hasConceptScore W2097042070C126322002 @default.
• W2097042070 hasConceptScore W2097042070C134018914 @default.
• W2097042070 hasConceptScore W2097042070C134651460 @default.
• W2097042070 hasConceptScore W2097042070C181199279 @default.

• next