Regulation of Highly Unsaturated Fatty Acid Metabolism
Cheon, Yewon
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Permalink
https://hdl.handle.net/2142/84955
Description
Title
Regulation of Highly Unsaturated Fatty Acid Metabolism
Author(s)
Cheon, Yewon
Issue Date
2008
Doctoral Committee Chair(s)
Wallig, Matthew A.
Nakamura, Manabu T.
Department of Study
Nutritional Sciences
Discipline
Nutritional Sciences
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Health Sciences, Nutrition
Language
eng
Abstract
Transcription factors, peroxisome proliferators activated receptor alpha (PPARalpha) and sterol regulatory element binding protein (SREBP)-1, are considered as the main regulators of fatty acid oxidation and synthesis, respectively, including metabolism of highly unsaturated fatty acids (HUFAs). The objective of the first project was to investigate functional differences of PPARalpha between species. PPARalpha is essential for adaptation to fasting in rats and mice. However, physiological functions of PPARalpha in other species are controversial. Peroxisome proliferators (PPs), PPARalpha ligands, cause peroxisome proliferation and hepatocareinogenesis only in rats and mice. To elucidate the role of PPARalpha in adaptation to fasting in non-proliferating species, we investigated the gene expression in pig liver in response to fasting and to clofibric acid (a PP) treatment, and evaluated the expression pattern against that of rats and mice. As in rats and mice, fasting and clofibric acid shared induction of genes involved with mitochondrial fatty acid oxidation and ketogenesis in pigs, indicating that PPARalpha mediates the induction of these genes. In contrast to rats and mice, neither noticeable induction of genes for peroxisomal or microsomal fatty acid oxidation nor significant hepatomegaly was observed in pigs fed clofibric acid. Therefore, PPARalpha is likely to play a central role in adaptation to fasting in pig liver as in rats and mice. The second project was to elucidate the role of phospholipid metabolism in the regulation of SREBP- 1 activation. Transcription of delta-6 desaturase (D6D), the key enzyme of HUFA synthesis, is regulated by SREBP-1. Dietary ethanolamine and eritadenine, which increase membrane PE/phosphatidylcholine (PC) ratio, suppress D6D mRNA and activity in rat liver. Therefore, we hypothesized that an increase in membrane PE/PC ratio suppresses D6D gene transcription by down-regulating SREBP-1 activation. Ethanolamine, eritadenine and HUFAs increased the PE/PC ratio in rat liver microsome and the change of PE/PC ratio was inversely correlated with both mature SREBP-1 and D6D mRNA in rat liver and in HepG2 cells. D6D promoter-luciferase assay in HepG2 cells demonstrated that sterol regulatory element is required for suppression of D6D transcription by ethanolamine and eritadenine. These results suggest that SREBP-1 activation may be regulated by the membrane PE/PC ratio.
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