The role of ascorbic acid in the regulation of cholesterol metabolism and in the pathogenesis of atherosclerosis

Strong clinical and experimental evidence suggests that chronic latent vitamin C deficiency leads to hypercholesterolaemia and the accumulation of cholesterol in certain tissues. Ascorbic acid supplementation of the diet of hypercholesterolaemic humans and animals generally results in a significant reduction in plasma cholesterol concentration. While most studies relating ascorbic acid to atherosclerosis have used the rabbit as a model, those concerned with elucidating the role of ascorbic acid in the regulation of cholesterol metabolism have generally used the guinea pig. Comparatively little use has been made of the non-human primates. A significant advance in recent years has been the development of a model of chronic latent scurvy in the guinea pig. Chronic dietary inadequacy of vitamin C may influence the pathogenesis of atherosclerosis as it affects not only plasma cholesterol and triglyceride concentrations but also the integrity of the vascular wall. Ascorbic acid is involved in the regulation of cholesterol metabolism in several ways. Dietary inadequacy of vitamin C is associated indirectly with a lowering of cholesterol absorption, this effect resulting from a reduction in the availability of bile acids, monoglycerides and fatty acids. The excretion of cholesterol as neutral steroids, however, appears not to be affected by ascorbic acid. Although much of the evidence for the involvement of ascorbic acid in cholesterol synthesis is equivocal, it seems likely that cholesterol synthesis is decreased in vitamin C deficiency. A series of studies using guinea pigs with chronic latent vitamin C deficiency has provided clear evidence that bile acid synthesis is reduced in this condition. Indirect evidence strongly suggests that this results from a decrease in the activity of the microsomal enzyme cholesterol 7α-hydroxylase. However, some evidence suggests that the mitochondrial reactions of bile acid synthesis require ascorbic acid. The role of ascorbic acid in the regulation of steroidogenesis appears to involve selective inhibitory and stimulatory effects on the desmolase, hydroxylase and dehydrogenase reactions which lead to the formation of pregnenolone and its subsequent conversion to steroid hormones.