Balogun, Kayode A. (2015) Lipid metabolism and the risk factors of cardiovascular disease: implication of dietary omega-3 polyunsaturated fatty acids. Doctoral (PhD) thesis, Memorial University of Newfoundland.
- Accepted Version
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Cardiovascular disease (CVD) is a complicated and multifarious disease, and is the number cause of mortality worldwide. The pathogenesis of CVD is attributed to the interaction between genetics and environment. There are numerous data that support the cardioprotective properties of omega (n)-3 polyunsaturated fatty acids (PUFA); however, there are also controversial reports. Considering the reported sex and age differences in the pathophysiology of CVD and the metabolism of n-3 PUFA, it is imperative to consider these factors in the cardioprotective effects of n-3 PUFA. The main objective of the current thesis was to investigate the effects of n-3 PUFA on the risk factors of CVD such as dyslipidaemia and obesity, with particular focus on how sex, age and dose of n-3 PUFA affect lipid and lipoprotein metabolism. The set of experiments presented in this thesis was investigated using the C57BL/6 mouse strain which has been established as a mouse model of choice for the study of diet-induced pathological conditions of lipid and lipoprotein metabolism. Plasma concentrations of lipids and lipoproteins of mice offspring at weaning and 16 weeks postweaning were chosen as study outcomes to assess the sex, age and dose-specific effects of n-3 PUFA on markers of dyslipidaemia, a well-known risk factor of CVD. It was observed that a longer exposure to a postnatal diet high in n-3 PUFA increased plasma concentration of low-density lipoprotein cholesterol (LDL-c) in the offspring in a sex-specific manner; however, the profile of this increase was less atherogenic , as the high n-3 PUFA group had a lower plasma concentration of very small LDL-particles in both males and females. There was no effect of high n-3 PUFA diet observed on plasma concentration of highdensity lipoprotein cholesterol (HDL-c); however, the high n-3 PUFA group had a higher cholesterol efflux in the male offspring but not in female offspring, further demonstrating the effect of sex on cholesterol metabolism. Lipidomic analyses revealed that high n-3 PUFA diet led to higher hepatic and plasma concentrations of n-3 PUFA-containing bioactive lipids such a phosphatidylcholine, lysophosphatidylcholine and free fatty acids, which could positively influence pathways involved in cardioprotection. The effects of dietary n-3 PUFA on obesity at the cellular level was also investigated, using adipocyte hypertrophy as the outcome measure of adipose tissue enlargement. A diet high in n-3 PUFA prevented adipocyte hypertrophy in males, with no effect in females. High n-3 PUFA diet also led to the downregulation of the mRNA expression of acyl CoA:diacylglycerol acyltransferase 2 (DGAT2), fatty acid binding protein-4 (FABP4), peroxisome proliferator-activated receptor protein γ (PPARγ), and leptin in males, which are key proteins involved in adipocyte hypertrophy; however no effect was observed in females. The last study assessed the effects of dose and duration of exposure to dietary n-3 PUFA on DHA accretion in the brain, and the expression of neurotrophins known to have neuroprotective and cardioprotective benefits. A diet high in n-3 PUFA led to an accretion of DHA in the brain cortex of the male offspring. Furthermore, dietary n-3 PUFA led to an agedependent increase in the expression of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase (TrKB), and phosphorylated cAMP response element binding protein (pCREB). Furthermore, there was a positive correlation between the cortical mRNA expression of BDNF and plasma concentrations of triglycerides and non-esterified fatty acids, suggesting a relationship between neurotrophins and regulation of lipid metabolism. In conclusion, the results from the current thesis demonstrate a sex, dose and age specific effect of n-3 PUFA on risk factors of CVD, and on novel regulatory pathways by which n-3 PUFA could reduce dyslipidaemia and obesity; the results also suggest that n-3 PUFA could be neuroprotective and cardioprotective through a common neurotrophin signalling pathway.
|Item Type:||Thesis (Doctoral (PhD))|
|Additional Information:||Includes bibliographical references. -- Title reads: "Lipid Metabolisim..."|
|Keywords:||Omega-3 polyunsaturated fatty acids, Cardiovascular disease, Sex, Dyslipidemia, Neurotrophins|
|Department(s):||Science, Faculty of > Biochemistry|
|Library of Congress Subject Heading:||Omega-3 fatty acids--Metabolism--Age factors; Cardiovascular system--Diseases--Nutritional aspects; Cardiovascular system--Diseases--Risk factors; Lipids--Metabolism; Lipoproteins--Metabolism|
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