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Plant sterols (PS) share a similar chemical structure to cholesterol, differing only in side chains and double bond placement. PS are naturally found in plants and are typically ingested in the 400mg/day range. Consumption of 1-3 g of PS a day has been repeatedly shown to lower total and LDL cholesterol. However, data from nutritional trials involving plant sterols demonstrate considerable inter-individual variations in response to PS consumption. The objective of this research was to investigate the metabolic and genetic factors that underlie this heterogeneity of responsiveness of LDL cholesterol to PS consumption. A study was conducted to test the effectiveness of lathosterol to cholesterol ratio (L/C), a surrogate marker of cholesterol synthesis, as a predictor of LDL cholesterol lowering in response to plant sterol consumption. 63 mildly hypercholesterolemic adults, with high (n=24, L/C = 2.03 ± 0.39umol/mmol) or low (n=39, L/C =0.99±0.28 umol/mmol) L/C ratio at baseline, consumed either 0 or 2g/d of PS for 28 days in a dual-center, single-blind, randomized, crossover design. Plasma lipid and non-cholesterol sterol concentrations were measured at the end of each phase. Single nucleotide polymorphisms (SNPs) in candidate genes involved in cholesterol metabolism were investigated for potential gene by nutrient interactions. Plant sterol consumption lowered total and LDL cholesterol concentrations overall, but only individuals with low L/C ratio responded to plant sterol treatment by lowering TC and LDL-C, while individuals with high L/C ratio showed no marked improvement. The rs3808607 T-allele in the promoter of the CYP7A1 gene was associated with decreased LDL-C responsiveness to PS consumption. The rs3808607 G-allele and ApoE ε4 were associated with increased LDL-C responsiveness to PS consumption. PS consumption did not lower TG overall (p=0.0506), but had an interaction with rs5882 in CETP (p=0.0080). Baseline L/C predicts LDL-C lowering due to PS consumption, which is associated with rs3808607 genotype in the promoter of the CYP7A1 gene. rs5882 in CETP is associated with TG lowering due to PS consumption. rs3808607, rs5882 and ApoE variant are potential genetic markers which could identify individuals who would derive maximum benefit from PS consumption.

Thesis (Ph. D.)--Columbia University, 1933. / Vita. Bibliography: p. 21-23.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1948. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 30-33).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1939. / Typescript. Includes abstract and vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references: leaves 51-53.

Thesis (M.S.)--Wisconsin. / Includes bibliographical references (leaves 124-134).

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2008. / Title from title screen (site viewed Mar. 10, 2009). PDF text: 100 p. : ill. ; 708 K. UMI publication number: AAT 3330677. Includes bibliographical references. Also available in microfilm and microfiche formats.

In Part I, hypotheses for the biogenesis of Erythrina alkaloids are discussed. Di-(β-3,4-dihydroxyphenyl)-ethylamine the theoretical precursor predicted by the biogenetic theory, was prepared and ring closure to the erythrinane ring system by oxidative coupling was attempted under various conditions. Consequently, the biogenesis of the Erythrina alkaloids was re-examined and a new proposal is advanced for the biosynthesis of these alkaloids. Synthetic routes to a hypothetical precursor, proposed here for the first time as a potential intermediate, are described. The biogenetic-type synthesis of the spiro-amine ring system present in the Erythrina alkaloids was achieved by oxidative coupling of the blocked diphenolic precursor, as predicted by the proposed biosynthetic scheme. Oxidation of di-(β-3-hydroxy-4-methoxyphenyl)-ethylamine by alkaline potassium ferricyanide afforded 3,15-dimethoxy-16-hydroxy-2-oxo-erythrina-1(6),3-diene in 15% yield. Reduction of the latter by sodium borohydride gave 3,15-dimethoxy-2,16-dihydroxyerythrina-l(6),3-diene. Acetylation of the dienone yielded 3,15-dimethoxy-16-acetoxy-2-oxoerythrina-1(6),3-diene. The total biogenetic-type synthesis of erysodine is therefore but two steps from completion. The results as a whole confirm the hypothesis that Erythrina alkaloids are produced in Nature by oxidative coupling of diphenols. They also demonstrate the directing role of the protective groups in the phenolic precursor. The evidence allows a biosynthetic pathway for the aromatic Erythrina alkaloids to be considered, and the mechanism for the ring closure process is discussed. The isotopically labelled precursor 3-hydroxy-4-methoxy-N-(3-hydroxy-4-methoxyphen[1-¹⁴C]ethyl)-phenethylamine was prepared to test the biosynthetic hypothesis in the plant. Feeding experiments are in progress. In Part II, the biogenesis of cholesterol and methods for functionalising inert methyl groups are reviewed, and a new theoretical approach to removal of the 14α-methyl group from lanosterol is described. The removal of this methyl group in vitro could not be achieved, but a series of interesting compounds was obtained. Evidence for the structures of these compounds is presented. Thus, photosensitized oxygenation of dihydrolanosteryl acetate in the presence of para-nitrobenzenesulphonyl chloride yielded 3β-acetoxylanosta-7,9(ll)-diene, 3β-acetoxylanost-8-ene-7-one and 3β-acetoxylanost-8-ene-7a-hydroperoxide. In addition a compound having an ambiguous structure and designated as IP1 was obtained. The dibromo-derivative of the latter is 33-acetoxy-7a,lla-dibromolanostane-8 a,9α-epoxide, the structure of which was determined by X-ray crystallographic study. A working structure for compound IP1 based on the physical and chemical evidence is discussed. / Science, Faculty of / Chemistry, Department of / Graduate

An in vivo technique was developed for the purpose of determining the rate of absorption of bile salts by the mesenteric small intestine of the chicken. Using this technique, it was found that the absorptive capacity of the intestine for sodium taurocholate and sodium glycocholate increases distally. The possibility was investigated that the amount of bile salt reabsorbed from the intestine determines the level of circulating sterols in the chicken. Intestinal absorption of sodium taurocholate was accordingly determined in birds selected to show a wide range in levels of circulating sterols. Absorption of the bile salt was tested with concentrations of taurocholate equivalent to 0.15 and 0.75% cholic acid, using open segments of intestine. Data obtained from 20 birds showed that the level of circulating sterols and the rate of bile salt absorption were not significantly correlated. The lack of a significant correlation was considered to be probably due in part to variation in the effect of diet on the availability of bile salts for reabsorption. The rate of bile acid excretion and the concentration of circulating sterols were therefore determined in birds fed diets supplemented with triglycerides, of varying degree of unsaturation, soyalecithin and beta sitosterol. It was found that a diet supplemented with 15% coconut oil induced an elevation in the level of plasma sterols when substituted for a low-fat diet but that diets supplemented with corn oil and herring oil, induced little or no change in this level. The change to a fat-enriched diet was associated with a decrease in the fecal output of bile acids. The decrease was greater when coconut oil rather than corn oil or herring oil was fed, indicating that the plasma sterol lowering property of unsaturated fats is due at least in part to their enhancing effect on bile acid excretion. Diets to which 2.5% soyalecithin and 0.5% beta sitosterol were added, effected a slight reduction in the level of plasma sterols. The addition of soyalecithin to the diet resulted in a significant increase (P < 0.01) in the growth rate of the birds studied. The amount of bile acids excreted was increased significantly (P < 0.01) by the addition of soyalecithin to the diet. The addition of beta sitosterol to the diet resulted also in an increase in bile acid excretion. The increase approached significance at the 5% level of significance (F ratio calculated = 7.53, significant F ratio = 7.71). The increase in bile acid excretion resulting from the administration of the soyalecithin supplemented diet was considered to be the net result of two opposing effects. One effect was an increase in the reabsorption of bile acids. It was evidenced by a further increase in the plasma sterol level of the lithocholic acid-fed chick in response to dietary soyalecithin. The other effect was reasoned to be an increase in the biliary excretion of bile acids and/or bacterial alteration of bile acids in the digestive tract. / Land and Food Systems, Faculty of / Graduate

The cells of two plants, Coffea arabica and an unknown Mentha species, were grown as suspension cultures in liquid media, in order to analyse and compare the fatty acids and sterols of the cell cultures to those found in the parent plants. The cell growth, the parameters of pH and conductivity of the media, and the composition of the neutral lipid fraction were examined. In the case of the coffee cell cultures, the cell growth and the media pH and conductivity were studied in three different media, two defined and one undefined, while the mint cell cultures were studied in one other defined medium. Both coffee and mint cell cultures were grown in the absence of light (normal cultural conditions) and in the presence of light. The coffee cells showed no differences in growth rate due to variations in media composition. Exposure to light affected neither the growth rate nor initiated chlorophyll formation in the coffee cell cultures, although a distinct green pigmentation formed in the mint cells. A plot of the ionic conductivity of coffee and mint cell suspension cultures was essentially a mirror image of the growth curve of the respective culture. The fatty acids present in the neutral lipid fraction of the cells were studied via gas chromatography, and were compared to the fatty acids found in the seeds and tissues of the parent plants. Palmitate, stearate, oleate, linoleate and linolenate were found in all coffee and mint cell cultures, independent of the composition of the media and of the presence of absence of light. The appearance of short chain fatty acids (less than C-l6) occurred during the dying phases of culture. The fatty acid composition of the coffee cell cultures resembled the analyses of the leaf and stem tissues of the coffee plant rather than the coffee bean. The cell cultures all contained linolenate, not found in the coffee bean, and lacked arachidate, which was present in the bean. In contrast to the coffee cell, the mint cell fatty acids resembled the fatty acid composition of the mint seed rather than the parent plant tissues which contained substantial quantities of the short chain fatty acids (less than C-16). The total fatty acid content of the coffee and mint cell cultures was lower than the seeds of the parent plant, but was comparable to parent plant tissues. A decrease in the total fatty acid content of the neutral lipid fraction of both cultures was noted during the death phase of culture. The total fatty acid content of the coffee cell cultures was not altered by changes in media composition, nor by growth of the cultures in the presence of light. However, the growth of mint cell cultures ln the presence of light had a marked effect on the fatty acid content, which increased approximately four fold in comparison to cultures grown in the dark. The sterol composition of the unsaponifiable lipid found in the extracts of coffee and mint cell cultures was investigated via gas chromatography and thin layer chromatography. The sterols present were compared to those found in the seeds of the parent plants. The sterols found in large concentration in the coffee cells werep -sitosterol, stigmasterol and campesterol, while in the mint cells only ϐ -sitosterol was conspicuous. The predominant sterols found in the seeds of the parent plants and in the plant cell cultures were identical. However, the cell cultures of both coffee and mint contained larger amounts of sterols in their saponified lipid extracts than found in the seeds. Furthermore, in comparison to the seeds, the lipid extracts of the cell cultures contained greater quantities of unesterified sterols. A wide variety of sterols other than desmethyl sterols were located in the seeds and cell cultures, but were not identified as they constituted only a minor portion of the total plant sterols present. A large portion of the unsaponiflables of the coffee bean was characterized as non-steroidal. This non-steroidal material was identified as a mixture of two diterpenold alcohols, cafestoi and kawheol, both known to be major constituents of the unsaponiflables of coffee bean oil. The coffee cell oil unsaponifiables were also found to contain these two diterpenoid alcohols. / Land and Food Systems, Faculty of / Graduate