Dietary oxysterols

Vine, D.F., Mamo, J.C.L., Beilin, L.J., Mori, T.A., Croft, K.D. 1998. Dietary oxysterols are incorporated in plasma triglyceride-rich lipoproteins, increase their susceptibility to oxidation and increase aortic cholesterol concentration in rabbits. J. Lipid Res. 39, 1995-2004. 

Oxysterols arise from dietary sources, non-enzymatic oxidation, and enzymatic oxidation reactions [19]. The structure of some of the oxysterols that may be involved in atherosclerosis are shown in Fig. 5. Dietary oxysterols are incorporated into chylomicrons and... 

K. D. (1998) Dietary Oxysterols Are Incorporated in Plasma Triglyceride-Rich Proteins, Increase Their Susceptibility to Oxidation and Increase Aortic Cholesterol Concentration of Rahhits, J. Lipid Res. 39,1995-2004. 

Several oxysterol classes present in oxLDL appear to be cytotoxic toward fibroblasts, ECs, and vascular smooth muscle cells, especially 7-hydroperoxycholes-terol (7-OOH-chol), 7P- and 7a-hydroxycholesterol (7-OH-chol), 7-ketocholesterol (7-keto-chol), and cholesterol epoxides (epoxy-chol). 7p-OOH-chol, a precursor of hydroxyl- and keto-oxysterols, was reported to be the most toxic. During LDL oxidation 7P-OOH-chol was produced in three to five times higher quantities than 7a-OOH-chol, other oxysterols and even hydroxy-nonenal, which is one of the most abundant lipid oxidation products. Cytotoxicity of oxysterols was connected to increased cellular oxidative stress. Some studies suggest that oxysterols are even involved in oxidative stress induction. Animal models indicate that dietary oxysterols can significantly decrease glutathione levels and increase expression of glutathione peroxidase and superoxide dismutase. In apolipoprotein-deficient mice, the NADPH-oxidase activity was induced by 7-keto-chol, 7p-OH-chol, and Sp,6P-epoxy-chol. The increased activity of NADPH oxidase yields more superoxide anions that amplify oxidative stress. 

Excess cholesterol can also be metabolized to CE. ACAT is the ER enzyme that catalyzes the esterification of cellular sterols with fatty acids. In vivo, ACAT plays an important physiological role in intestinal absorption of dietary cholesterol, in intestinal and hepatic lipoprotein assembly, in transformation of macrophages into CE laden foam cells, and in control of the cellular free cholesterol pool that serves as substrate for bile acid and steroid hormone formation. ACAT is an allosteric enzyme, thought to be regulated by an ER cholesterol pool that is in equilibrium with the pool that regulates cholesterol biosynthesis. ACAT is activated more effectively by oxysterols than by cholesterol itself, likely due to differences in their solubility. As the fatty acyl donor, ACAT prefers endogenously synthesized, monounsaturated fatty acyl-CoA. 

The proposed roles of oxysterols in atherosclerosis are based primarily on the results of cell-culture experiments. There are a number of in vivo studies in which investigators have exposed animals to oxysterols through diet or injection, but the overall results are not conclusive. For example, in a review by Brown and Jessup [19] of 13 oxysterol dietary studies, 6 showed an increase in atherosclerosis, but 4 demonstrated a decrease in lesion size and 3 showed no effect. Differences in animal models and types and doses of oxysterols undoubtedly account for some of these differences. 

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