Cholesterol biosynthesis rabbit

Recently nicotinic acid has been found to lower serum cholesterol in hypercholesteremia, and also in normal persons and rabbits (A3, F2). It was shown that the hypercholesteremia, induced by a 48-hour fast, could be completely corrected by giving the animals large doses of nicotinic acid during the fast. In contrast to nicotinic acid, nicotinamide does not lower the cholesterol level (M10). Several explanations are offered for the action of nicotinic acid (1) it inhibits cholesterol biosynthesis, (2) it interferes with coenzyme A, and (3) it involves a hitherto unknown pharmacologic effect. The renewed clinical interest in nicotinic acid induced us to look for a more specific and sensitive assay for nicotinic acid (B7, M8). 

The possibility that the biosynthesis of bile acids is regulated by a negative feedback mechanism was supported by early experiments by Thompson and Vars [206] and Eriksson [207], who showed that the rate of bile acid synthesis in rats increased about 10-fold when a bile fistula is made. Bergstrom and Danielsson demonstrated that duodenal infusion of taurochenodeoxycholic acid in bile fistula rats restored the increased synthesis to a normal rate [208]. Danielsson et al. [44] showed that the cholesterol 7a-hydroxylase activity increased in parallel with the bile acid synthesis after cannulation of the bile duct in rats. In a subsequent work by Mosbach et al., it was reported that the incorporation of isotope from labelled acetate, mevalonate and cholesterol but not from labelled 7a-hydroxycholesterol into bile acids was inhibited by duodenal infusion of taurocholate to bile fistula rats [209]. The incorporation of isotope from labelled acetate, mevalonate and cholesterol but not from labelled 7a-hydroxycholesterol was stimulated in perfused livers of cholestyramine-treated rabbits [210]. It was concluded that there are essentially no rate-limiting steps beyond 7a-hydroxycholesterol in the biosynthesis of bile acids from acetate. Since both cholesterol and bile acid biosynthesis was subjected to negative feedback inhibition by bile acids, it cannot be excluded that inhibition of cholesterol biosynthesis precedes inhibition of the bile acid biosynthesis, and that the latter inhibition is secondary to the former. 

Several target enzymes in the cholesterol biosynthesis pathway have been targeted in attempts to lower blood cholesterol. The HMG-CoA reductase inhibitor (106) is 10 times more potent than lovastatin <93JMC3658>, and both SQ-33600 (107) and XU 62-320 (108) also inhibit this enzyme . The indole compound SaH 57-118 (109) inhibits acyl CoA cholesterol acyltransferase and lowers cholesterol absorption in rabbits by 65% . 

Diverse effects on hpid metabohsm of the following steroidal substances have been reported in the literature. The effect of dihydrocholesterol, Zl -cho-lestanone, ergosterol and sitosterol on the sterol content of plasma and on cholesterol biosynthesis has been reviewed by Hess [371]. Recently Aramaki and co-workers [372] described the hypocholesterolemic action of cholestane-3j8,5a,6j8-triol (CLVII) in cholesterol-fed rabbits. The most effective dose of CLVII was about 170mg/kg/day. 

Several studies, in part contradictory, are available concerning the influence of nicotinic acid on cholesterol biosynthesis. Perry (1960) reported from work with rat liver slices a decreased incorporation of C-acetate into cholesterol with high concentrations of nicotinic acid in the medium Schade and Saltman (1959) had obtained similar results in rabbits fed with nicotinic acid. On the other hand, Merrill and Lemley-Stone (1957) found increased cholesterol synthesis in liver slices of rats fed nicotinic acid, while Duncan and Best (1960) reported that nicotinic acid has no effect on C-acetate incorporation. Parsons (1961 a) studied the effects of nicotinic acid and niacin on incorporation of C-acetate in man, and stated that considerably less conversion into serum cholesterol (free and esterifled) and into erythrocyte cholesterol occurred during nicotinic acid administration. The concept of inhibition of cholesterol synthesis is also held by Goldsmith (1962) the point of inhibition supposedly occurs before the formation of squalene, because sterol intermediates between squalene and cholesterol could not be detected in serum. 

Reviews of the literature reveal numerous studies on atherosclerosis are concerned with cholesterol, its presence in or absence from the diet, its synthesis and catabolism, and its distribution among plasma and various tissues. Epidemiological studies in man suggest that diet -high in fat or cholesterol along with fat - plays a prominent role in the human atherosclerotic disease. Cholesterol, linked to the disease by its presence in the atherosclerotic plaques and its effect in diets of animals, iS derived both from diet and by biosynthesis in body tissues. Rats and rabbits, so often used in laboratory studies, differ greatly in susceptibility to atherosclerosis and may well be quite different from humans in this respect. Even on semi-synthetic diets, containing no added cholesterol, rabbits develop atherosclerosis, whereas they do not on stock diets. Furthermore, the plasma cholesterol of rabbits is more easily altered than that of rats, whereas the cholesterol synthesis rate (from acetate) varies widely in rats in response to various diets. 

Ntanios, F.Y. and Jones, P. J. H. 1999. Dietary sitostanol reciprocally influences cholesterol absorption and biosynthesis in hamsters and rabbits. Atherosclerosis 143, 341-351. 

The influence of cholesterol on thromboxane biosynthesis was briefly mentioned above. Cholesterol-rich platelets were shown to release more arachidonic acid than cholesterol-depleted ones upon stimulation with thrombin, and the subsequent conversion of the precursor into TXBj was also higher in the cholesterol-rich platelets [167], An increased thromboxane production from platelets in vivo in the rabbit has also been demonstrated after a cholesterol-rich diet [187]. 

It is difficult to study hormonal factors regulating bile acid synthesis in intact animals because effective stimuli are counteracted by homeostatic mechanisms. Recently (36), effects of cortisone on bile acid production and biosynthesis were studied using the isolated, perfused rabbit liver (37), which offers a less complex system in which bile is easily sampled. When the donor rabbits were pretreated with cortisone acetate (3 mg/kg, intramuscularly) for 3 days, secretion of glycocholate during a 2.5-hr perfusion increased two-to threefold. The incorporation of acetate-1- C into bile acids was likewise increased, suggesting that part of the stimulatory effect was due to an increase in bile acid biosynthesis. Biliary cholesterol concentration (but not de novo... 

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