Thesis (Ph. D.)--University of Hong Kong, 1994. / Includes bibliographical references (leaves 293-306).

Thesis (Ph.D.)--McMaster University, 2004. / Adviser: Bernardo Trigatti. Includes bibliographical references (leaves 153-178). Also available online.

Obesity and metabolic dysfunction are worldwide health epidemics and they have grown to unprecedented levels. Human NAFLD is directly linked to obesity and metabolic dysfunction, so attention was given to elucidating a more complete understanding of the liver's role in mediating the metabolically healthy obese phenotype and to better characterizing the potential contribution of dietary fat and fatty acids as a therapeutic supplement to obesogenic diets. Specifically, flaxseed is high in α-linolenic acid (ALA; 18:3 n-3) and low in linoleic acid (LA; 18:2 n-6), and contains multiple other components such as fiber and lignans, and was investigated for its high potential to modify obesity phenotype and fatty liver disease. Additionally, we explored the temporal effect of initiating high-fat diets in various phases of adulthood. However, work in this field is complicated by an ongoing search for appropriate preclinical animal models of NAFLD as they have not been able to replicate the full spectrum of human NAFLD. As such, this dissertation sought to explore fatty liver disease in popular murine models of overnutrition, as well as a novel hen model. Major findings from this work showed that (1) exposure to a high-fat diet during early adulthood preserves metabolic homeostasis, modifies liver morphology, and protects against obesity-related disease, (2) dietary enrichment with flaxseed is capable of increasing tissue n3PUFA content, but this appeared to be only weakly related to metabolic and histological outcomes, and (3) there are limitations to the laying hen as a model of NAFLD as the pathogenic changes may not adequately match the human condition.

PUFAs have been shown to modulate ALD by several mechanisms, including free radical generation from hepatic lipid peroxidation. However, how they modulate lipid peroxidation and generation of bioactive metabolites in ALD is poorly understood and it is still not clear which PUFAs (ω-3 or ω-6) are beneficial or detrimental in ALD. Thus, our objective was to study the effect of ω-3/ω-6 PUFAs on lipid peroxidation and ethanol mediated steatosis and inflammation. Using standard liquid diet (LDC), LDC with fish oil (rich in ω-3) and safflower oil (rich in ω-6), we studied the generation of bioactive metabolites, such as eicosanoids and free radicals generated via lipid peroxidation. In addition, we determined the effect of PUFAs on several inflammatory and fibrotic factors, e.g. gene as well as protein expression, using western blot and RT-PCR, respectively. We also investigated the effect of PUFA diets on novel targets, such as hepatic membrane transporters with potential role in liver inflammation. Our results suggest that ω-3 diet prevented while ω-6 based diets promoted the development of fatty liver and inflammation. ω-3 PUFA reduced AA-peroxidation by lowering hepatic AA concentration and expression of peroxidation enzymes, COX-2 and 5-LOX, resulting in lower generation of pro-inflammatory AA-derived PGs (Series-2), HETEs and free radicals, along with increase in anti-inflammatory EPA and DHA-derived PGs (Series-3). ω-3 diet might also reduce liver inflammation by preventing activation of NF-кB and induction of TNF-α. Rats fed with ω-3 diet showed high protein expression of efflux transporters, MRP-2 and ABCA1, indicating elimination of peroxidation metabolites and triglycerides from the liver and decreased inflammation. In contrast, ω-6 diets led to increase in AA-peroxidation and generation of AA-derived pro-inflammatory metabolites. ω-6 based diets also promoted fatty liver and inflammation by activating NF-кB, inducing TNF-α and downregulation of efflux transporters, MRP-2 and ABCA1. This study not only provides new insights into the effects and possible mechanisms by which ω-3 and ω-6 PUFAs may alter hepatic steatosis and inflammation, but also put forward new targets of research, such as hepatic membrane transporters in relation to liver pathology in ALD.

Gas chromatographic acquisition of representative 'Total' cellular fatty acid profiles from bacteria or bacteria-containing samples (e.g., environmental or clinical materials) tends to be dependent on the method used to released the fatty acids and convert them to derivatives suitable for analysis. Alkaline saponification or interesterification methods, while preserving acid-sensitive components such as cyclopropane fatty acids, are often insufficient to release amide-linked components, such as hydroxylated fatty acids. Acid-catalyzed hydrolyses or interesterifications, on the other hand, while more efficiently releasing the predominantly amide-linked hydroxylated components, have been shown to cause severe and unpredictable degradation of cyclopropane fatty acids. We report studies of a single-tube method involving sequential alkaline/acid release of fatty acids in which fatty acids released by the alkaline step are partitioned into an organic epiphase during the aqueous acid hydrolysis step. After hydrolysis, the epiphase and the released fatty acids are extracted into an hypophasic solvend and esterified at moderate temperature under relatively low acid concentrations. Under these conditions, cyclopropane as well as hydroxylated fatty acids are recovered in high yield.

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published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy