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Marginal Vitamin C Deficiency, Lipid Metabolism and Atherogenesis

The liver microsomes of these species lack the enzyme of the last stage of ascorbate biosynthesis, gulonolactone oxidase (Burns, 1957). This is assumed to be a specific genetic limitation, mutation of the operon responsible for synthesis of this enzyme. For most of these species, this genetic disturbance is not a real danger, as they are herbivores inhabitating tropical or subtropical regions with an abundant supply of vitamin C the whole year round. The species most seriously affected by this mutation is Homo sapiens, who inhabits the whole of the globe, including regions where the supply of food rich in vitamin C is limited for part of the year. Although advances in agriculture, transport and storage techniques have largely abolished the danger of scurvy (acute vitamin C deficiency), there are probably still, even now, in the second half of the 20th century, millions of people who suffer from marginal vita min C deficiency for at least part of the year. The aim of this review is to sum up data on the effect of vitamin C deficiency on the metabolism of cholesterol, triglycerides, and various components of the blood vessel wall and to draw attention to the fact that latent vitamin C deficiency (hypo- vitaminosis C) must be regarded as a risk factor in association with atherosclerosis.


Individual phases of acute avitaminosis often differ completely in respect of even such basal parameters as nitrogen balance, for example (Ginter, 1970b). The terminal phase of acute avita minosis C is an immensely complicated pathological state, very hard to role is played by many nonspecific factors, such as the abrupt drop in body weight, a negative nitrogen balance, and hemorrhage in various parts of the body.

Alongside vitamin C deficiency, a decisive In the first stage of avitaminosis C, very pronounced accumulation of esterified (and hence of total) cholesterol occurs in guinea pig adrenals. As scurvy develops, the cholesterol level returns to normal
and it is not until the terminal stages, when body weight falls, that the adrenal-cholesterol concentration drops below the control values . In avitaminosis C, the function of the tricarboxylic acid cycle is impaired , resulting in slower oxidation of acetate to C02. The incorporation of [l-14C]acetate into the liver glycogen and adipose tissue fatty acids of scorbutic guinea pigs is also slower. Some authors attribute elevated cholesterol accumulation in the body of scorbutic guinea pigs to raised utilization of the acetate pool for cholesterol synthesis or to reduced transformation of cholesterol to bile acids in their liver. The extremely intricate situation in lipid metabolism is complicated still further by the fact that hypoinsulinism develops in guinea pigs with acute scurvy.

Acute scurvy is rare in civilized human societies, whereas latent vitamin C deficiency is very common. Since acute scurvy and latent vitamin C deficiency are two metabolically very different states.

Unlike man, the rabbit synthesizes ascorbate, however, and actually reacts to a supply of exogenous cholesterol by an increase in vitamin C synthesis.Homeostasis of ascorbate levels in the blood and tissues is exceptionally highly developed in the rat, so that neither the addition of 1% ascorbic acid to a balanced diet, nor its omission from the diet, affects the ascorbate levels in the organs except the kidneys (Ginter, 1975b). Under these conditions, serum- and tissue- cholesterol concentrations are naturally likewise unaffected. For studying the influence of vitamin C deficiency on hypercholesterolemia and atherosclerosis, it is thus obviously necessary to use animals dependent, like man, on exogenous vitamin.

If latent vitamin C deficiency lasted longer than 3 months, however, cholesterol always accumulated in the guinea pig liver and hyper cholesterolemia developed. The hypercholesterolemic action of vitamin C deficiency depends on the lipid composition of the diet. A vitamin C-free diet containing 12.5% cottonseed oil leads to hypercholesterolemia in guinea pigs in only 2 weeks, while the addition of 5% coconut oil potentiates the hypercholesterolemic effect of ascorbate deficiency still further. The hypercholesterolemic action of vitamin C deficiency depends on the lipid composition of the diet. A vitamin C-free diet containing 12.5% cottonseed oil leads to hypercholesterolemia in guinea pigs in only 2 weeks, while the addition of 5% coconut oil potentiates the hypercholesterolemic effect of ascorbate deficiency still further. In some tissues, cholesterol levels are graduated in correlation to the dose of ascorbic acid, and in some tissues there is a significant negative correlation between the cholesterol concentration and the ascorbate level, i.e., the higher the ascorbate level, the lower the cholesterol concentration, and vice versa.

Vitamin C deficiency did not markedly affect endogenous cholesterol synthesis in the liver.. In vivo experiments were rather indicative of elevated cholesterol synthesis in ascorbate-deficient baboons, however. Excration of [14C]bile acids in the stools was smaller in vitamin-deficient guinea pigs. This result indicated that the rate of cholesterol transformation to its principal catabolic product, bile acids, is slowed down in marginal vitamin C deficiency. Cholesterol
is transformed to bile acids in the liver and the rate of this process very probably depends on the ascorbate concentration in the liver cells, since there is a relatively close linear correlation between the rate of bile acid synthesis and the ascorbic acid concentration in the liver (Fig. 8). Cholesterol transformation to bile acids is a multistage process taking place successively in the liver cell microsomes, supernatant fraction, and mitochondria. It involves hydroxylation, dehydrogenation, saturation of a double bond in the nucleus, 3-ketone reduction, and «- and /3-oxidation of the cholesterol side chain.The transformation of cholesterol to the
principal bile acid of guinea pigs, chenodeoxycholic acid, entails two hydroxylations: at position la in the cholesterol nucleus and at position 26 on its side chain... It seems therefore highly probable that marginal vitamin C deficiency interferes with the biosynthesis
of bile acids solely at the stage of 7a-hydroxylation of the cholesterol nucleus. It seems feasible that the stimulant effect of ascorbate on the 7a-hydroxylation of cholesterol is mediated through its action on the cytochrome P-450 level in the liver microsomes.

The strong influence of vitamin C on the liver is manifested not only in the transformation of cholesterol to bile acids, but also in detoxication of a variety of pharmacological agents and environmental chemicals (Zan- noni and Sato, 1975; Street and Chadwick, 1975), in which microsomal cytochrome P-450 plays a role, as in 7«-hydroxylation of cholesterol. Chronic latent ascorbate deficiency is associated with morphological, as well as functional, changes in the liver cell, the chief one being marked
reduction and replacement of the granular endoplasmic reticulum (Sulkin and Sulkin, 1975) (Fig. 14). In protracted marginal vitamin C deficiency, guinea pig liver displays centrolobular fatty degeneration, moderate hyperplasia of the bile ducts and occasionally discrete signs of fibroplasia (Fig. 15). Fatty cirrhosis, with bile duct proliferation, was even observed in the liver of hypovitaminous guinea pigs fed on a diet containing 0.3% cholesterol (Fig. 16). The pathological changes in animals given the same cholesterol diet, plus 100 mg ascorbic acid/animal/day, were less striking.

Chronic marginal vitamin С deficiency is associated with a sharp decline in the liver ascorbate concentration, with a consequent decrease in the rate of cholesterol transformation to bile acids. Lowered bile acid synthesis is associated with lowered absorption of exogenous cholesterol from gastrointestinal tract, but this homeostatic mechanism is not sufficiently effective to be able to compensate slower cholesterol catabolism in full. This creates a state of imbalance, in which the supply of cholesterol to the system exceeds the rate of its removal, resulting in the accumulation of cholesterol in the liver and plasma. If marginal vitamin C deficiency is protracted (5-6 months), the guinea pig liver-cholesterol above the control values.


In golden hamsters, which are normally independent of exogenous vitamin C, relative ascorbate deficiency was induced by administering a physiologically unbalanced fat-free, ascorbate-free, high glucose diet. these animals, just as in vitamin C- deficient guinea pigs, the plasma and liver cholesterol concentration rose compared with the group given the same diet plus 0.5% ascorbic acid, the half-life of plasma and liver cholesterol was prolonged, the size of the body pool of miscible cholesterol increased, the fractional turnover rate fell and the rate of cholesterol transformation to bile acids diminished
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Miodrag Milić's profile photoLouis George's profile photo
 
Drawing a conclusion from this review is difficult, especially if I'm trying to extrapolate to humans.
Still, getting people to consume atleast RDA of ascorbate seems to be a good idea.
Coconut oil making hyperlipidaemia worse in marginal vit c deficiency? albeit, in animal models, is a little scary.
All my cooking is in coconut oil.
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