Oxysterols

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• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584645/
• http://ajcn.nutrition.org/content/66/5/1240.long
• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931500/

• In water, cholesterol oxidizes more rapidly. But at 125°C, autoxidation of cholesterol also occurs in the dry state.[1]
• Cholesterol incorporated in a membranes is relatively protected aginst oxidation.[2]
• Heating at 100°C for 8 hours, 5% of cholesterol was oxidized. The identified oxidation products (52% of total) were: 7-ketocholesterol (42%), 7β-hydroxycholesterol (20%), β-epoxycholesterol (16%), α-epoxycholesterol (12%), 7α-hydroxycholesterol (7%) and 25β-hydroxycholesterol (3%).[3]
• oxidized fatty acids in the diet contribute to serum lipoprotein oxidation.
• oxidized fatty acids in the diet accelerate atherosclerosis in cholesterol-fed rabbits.[4]
• Serum cholesterol is increased after consuming unoxidized cholesterol, similar to partially (5%) oxidized cholesterol, but only the oxidized cholesterol (25 mg/day) diet resulted in a 100% increase in fatty streak lesions in the aorta.[5]
• Cholesterol oxidation products are not equally distributed among plasma lipoproteins.[6][7]
• Elevated levels of oxidized LDL correlate with subclinical atherosclerosis and predict future cardiovascular events [8]Free Full Text [9]Free Full Text
• oxidized β-VLDL is degraded by macrophages at an accelerated rate compared with native β-VLDL.[10][11]
• oxidized β-VLDL leads to increased lipid accumulation in smooth muscle cells.[12][13]

Fred Kummerow

Oxysterols (25- and 26-hydroxycholesterol) have an injurious effect on arterial cells. [14] The arteries from patients who had had coronary artery bypass operations, contained elevated concentrations of oxysterols and sphingomyelin, increasing calcium influx into endothelial cells. The phospholipd sphingomyelin fraction in replaced arteries was 48.2%, compared to 24% in healthy arteries, and to 10% in arterial tissue from umbilical cords. [15]

the newborn human placenta contained only about 10% sphingomyelin and 50% phosphatidylcholine.

"But when we looked at the arteries of people who had had bypass operations, we found up to 40% sphingomyelin and about 27% phosphatidylcholine," Kummerow said. "It took us many more years to discover that when you added large amounts of oxysterols to the cells, then the phosphatidylcholine changed to sphingomyelin."

Further evidence supported sphingomyelin's starring role in atherosclerosis. When Kummerow and his colleagues compared the blocked and unblocked arteries of patients needing second bypass operations, they found that the arteries with blockages contained twice as much sphingomyelin as the unblocked arteries. The calcium content of the blocked arteries (6,345 parts per million) was also much higher than that of the unblocked arteries (182 ppm).

Other studies had demonstrated a link between increases in sphingomyelin and the deposit of calcium in the coronary arteries. The mechanism by which this occurred was unclear, however. Kummerow's team searched the literature and found a 1967 study that showed that in the presence of certain salts (in the blood, for example), lipids like sphingomyelin develop a negative charge. This explains the attraction of the positively charged calcium to the arterial wall when high amounts of sphingomyelin are present, Kummerow said.

"So there was a negative charge on the wall of this artery, and it attracted calcium from the blood until it calcified the whole artery," he said.

Oxidized fats contribute to heart disease (and sudden death from heart attacks) in an additional way, Kummerow said. He and his collaborators found that when the low-density lipoprotein (LDL, the so-called "bad cholesterol") is oxidized, it increases the synthesis of a blood-clotting agent, called thromboxane, in the platelets. [16]

Oxidized cholesterol (oxysterols) enhances the production of sphingomyelin, a phospholipid found in the cellular membranes of the coronary artery. This increases the sphingomyelin content in the cell membrane, which in turn enhances the interaction between the membrane and ionic calcium (Ca2+), thereby increasing the risk of arterial calcification. Patients undergoing bypass surgery had greater concentrations of oxysterols in their plasma than cardiac catheterized controls with no stenosis, and had five times more sphingomyelin in their arteries than in the artery of the placenta of a newborn. The oxysterols found in the plasma of these patients were also found in the plasma of rabbits that had been fed oxidized cholesterol and in frying fats and powdered egg yolk intended for human consumption. Together these findings suggest that oxysterols found in the diet are absorbed and contribute to arterial calcification. Oxidized low-density lipoprotein (OxLDL) further contributes to heart disease by increasing the synthesis of thromboxane in platelets, which increases blood clotting. Cigarette smoke and trans fatty acids, found in partially hydrogenated soybean oil, both inhibit the synthesis of prostacyclin, which inhibits blood clotting. By increasing the ratio of thromboxane to prostacyclin, these factors interact to interrupt blood flow, thereby contributing to heart attack and sudden death. Levels of oxysterols and OxLDL increase primarily as a result of three diet or lifestyle factors: the consumption of oxysterols from commercially fried foods such as fried chicken, fish, and french fries; oxidation of cholesterol in vivo driven by consumption of excess polyunsaturated fatty acids from vegetable oils; and cigarette smoking. Along with the consumption of trans fatty acids from partially hydrogenated vegetable oil, these diet and lifestyle factors likely underlie the persistent national burden of heart disease. [17]