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Title: Exploring mechanisms of action of flavonoids and phenolic acids on pathways of lipid metabolism
Author: Kerimi, Asimina
ISNI:       0000 0004 2740 6246
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2011
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Epidemiological studies- indicate an association between the consumption of a 'diet rich in polyphenols and several health benefits. As diabetes and other lipid associated diseases are now reaching menacing proportions worldwide, the need for the development of cost-efficient prevention strategies effective at the population level becomes more essential than ever. Studies in the biological effects of polyphenols are now starting to include their hypoglycaemic and hypolipidemic properties and to investigate potential mechanisms through which they may exert their actions. The focus of the present study was to examine the action of various flavonoids and phenolic acids in pathways of energy metabolism and how they may affect the gene expression of critical enzymes involved in lipid and glucose metabolism. Studied flavonols (quercetin, kaempferol, galangin), and coffee phenolic acids and their metabolites (caffeic acid, dihydroferulic acid, protocatechuic acid) were identified as novel regulators of CPTIA, while quercetin was found to importantly upregulate CPTIA & PDK4 gene expression, to restrict glucose uptake and citrate synthase activity, and therefore was shown to potentially modulate energy metabolism in HepG2 cells. Dihydroferulic acid, the main microbial metabolite of chlorogenic acids from coffee was found to significantly increase PDK4 mRNA levels and enhance citrate synthase activity while it increased glucose uptake. On the other hand, a mixture of flavonols at in vivo relevant concentrations was able to produce a synergistic upregulating effect on CPTIA & PDK4, similar to that observed with quercetin, but an increase in glucose uptake. Further studies showed that the induction of CPTIA and PDK4 by quercetin was mediated by more than one transcription factors, with AMPK to have a pivotal role but Nrf2 driven antioxidant mechanisms not to be involved. From our data we hypothesised for quercetin that it sets the cell under a similar with mild starvation state as in between meals. Phenolic acids were further studied for their role in p-oxidation processes and it was demonstrated for the first time that they may form intermediates of p-oxidation as part of their metabolism in HepG2 cells. Our data suggest a novel but distinct role between flavonols and phenolic acids in lipid metabolism. Their action is defined both by direct interactions with enzymes involved in p-oxidation as well as by indirect actions on the transcriptional level. The biological importance of these findings requires further studies with additional models, which will expand our knowledge with regards to the role of polyphenols in lipid metabolism and any possible beneficial in vivo effects. III
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available