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Dietary Peroxidized Lipids and Intestinal Apolipoprotein Synthesis

Jiang, Xueting
http://rave.ohiolink.edu/etdc/view?acc_num=osu1397660120

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Human Ecology: Human Nutrition.
The goals of this project are to investigate the metabolic fate of free fatty acid peroxide and its decomposition products in the presence of intestinal cells and to determine their roles in apolipoprotein synthesis by intestinal and hepatic cells. Oxidative stress and peroxidized lipids are seen as harmful molecules with respect to cardiovascular diseases. Most of these reports come from studies on systemic lipid peroxidion. Diet plays a major role in the development of atherosclerosis, a major form of cardiovascular disease. Peroxidized lipids and their degradation products are generated in the diet as a result of prolonged exposure to air, heating, and perhaps due to high content of polyunsaturated fatty acids in some cooking oils. Both pro- and anti-atherosclerotic effects have been ascribed to the dietary presence of peroxidized lipids. For example, a significant number of in vitro and in vivo studies indicate an activation of the synthesis of apolipoprotein A1, a major component of the beneficial lipoprotein HDL and a decrease in plasma triglyceride (TG). In contrast, dietary peroxidized lipids have been shown to increase atherosclerosis in cholesterol fed mouse models of atherosclerosis, and to even increase in plasma lipids. Peroxidized lipids readily decompose to a variety of products, including hydroxides, aldehydes, ketones, and carboxylic acids. There is a void of knowledge in the understanding of when to expect harmful effects and when the beneficial effects could be realized. The effects of some of the decomposition products were poorly studied. Understanding of how dietary oxidized lipids are metabolized by the intestinal cells could help to eliminate the pro-atherosclerotic effects while retaining the beneficial components. Free linoleic acid peroxide (hydroperoxycotadecadienoic acid, 13-HPODE) was used in the study. Results presented in this thesis would indicate that in the presence of Caco-2 cells, 13-HPODE was rapidly reduced to hydroxides (13-HODE) as a result of loss of peroxide function. Upon entering the cell, 13-HODE appears to undergo esterification. HPODE also underwent auto-decomposition to generate aldehydes as well. In this study, I focussed on the decomposition product from the carboxylic end of the fatty acid chain, namely 9-oxononanoic acid (ONA). ONA is not commercially available. I synthesized non-radioactive and radioactive forms of ONA to determine whether this toxic aldehyde could be converted to beneficial AzA. The latter compound has been known to be anti-inflammatory and anti-atherogenic. I found that ONA was oxidized to AzA rapidly in the cell medium and AzA was poorly absorbed by intestinal cells and stayed stable in the cell medium for up to 18 hours. HPODE, ONA and AzA were used to treat poorly differentiated, fully differentiated Caco-2 and HepG2 cells. The former lacks the absorbing surface brush border and the later expresses markers of differentiation and the brush border architecture. An increased ApoA1 secretion was observed in Caco-2 cells by ELISA and Western blot whereas such induction was not observed in HepG2 cells. However, HPODE treatments suppressed PON1 activity in the medium as measured by p-nitrophenyl acetate hydrolysis suggesting the induced secretion of ApoA1 by HPODE may not represent functional HDL. On the other hand, AzA induced both ApoA1 secretion and PON1 activity while suppressing ApoB secretion in fully differentiated Caco-2 cells but not in HepG2 cells. HPODE and ONA were also found to supress ApoB secretion by differentiated Caco-2 cells. A marginal modulation at mRNA level was noticed suggesting the existence of intestine specific post-translational regulation. These results suggested that sustaining the oxidation to AZA levels might be important in the beneficial actions of dieteray peroxidized lipid derived aldehydes. This is the first study to address the metabolic fate of ONA and AzA in the intestine. Our current results indicated that the anti-atherogenic effects of AzA might be important and might relate to the increased apoA1 and PON activation, among other effects. Considering that not much uptake of AZA was seen could indicate a potent cellular effects, perhaps mediated by specific saturable uptake mechanisms and signaling events. Our data also pointed that intestine can be a novel target for anti-atherogenic drug as it represented a significant part of ApoA1, PON1 and ApoB in circulation. Our study also provided evidence that intestine has its own regulation of lipoprotein secretion that is distinct from liver.
Sampath Parthasarathy (Advisor)
164 p.
Nutrition
Caco-2, ApoA1, HPODE, lipid peroxidation, ApoB, PON1, Oxononanoic acid, azelaic acid,

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Citations

  • Jiang, X. (2014). Dietary Peroxidized Lipids and Intestinal Apolipoprotein Synthesis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397660120

    APA Style (7th edition)

  • Jiang, Xueting. Dietary Peroxidized Lipids and Intestinal Apolipoprotein Synthesis. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1397660120.

    MLA Style (8th edition)

  • Jiang, Xueting. "Dietary Peroxidized Lipids and Intestinal Apolipoprotein Synthesis." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1397660120

    Chicago Manual of Style (17th edition)

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