Effect of excess dietary cystine on the biodynamics of cholesterol in the rat.

Ingestion of an excess level of 5% of L-cystine produced in the rat the following effects: total cholesterol concentration was increased in the plasma (from 102 to 165 mg/100 ml) and body (from 133 to 184 mg/100 g) whereas esterified cholesterol level was decreased in the liver (from 151 to 59 mg/100 g). The absorption coefficient of dietary cholesterol and the external secretion (elimination in the feces of cholesterol biosynthesized in the intestine) were not changed. The urinary and fecal excretion, transformation into bile acids and input into the plasma of cholesterol biosynthesized in the organs (internal secretion) were enhanced. The elevation of cholesterol synthesis in the cystine-treated rats was explained by an increased hepatic cholesterol synthesis. Hence, addition of cholesterol, which inhibits hepatic cholesterol synthesis, to the cystine-enriched diet led to a significant decrease (by 50%) in cholesterol synthesis. Moreover, when the absorption coefficient of dietary cholesterol was decreased (replacement of lard by tristearin) cholesterol synthesis of the cystine-fed rats was increased. Thus, such a relationship, previously demonstrated for rats in which the intestine was the major source of biosynthesized cholesterol, exists also when the liver becomes more important in the synthetic process.

A new relationship between cholesterolemia and cholesterol synthesis determined in rats fed an excess of cystine.

The present study deals with an attempt to describe how the plasma cholesterol level is related to input into the plasma of cholesterol synthesized in the liver and in the intestine. It has previously been shown in our laboratory that, for a given absorption of alimentary cholesterol, the rat plasma cholesterol level decreases when internal secretion of cholesterol (cholesterol synthesized in the organs and poured into the plasma) increases. This relationship was established using rats in which the major source of cholesterol synthesis was the intestine. We used rats fed a cystine-enriched diet (5%) which was previously shown to increase cholesterolemia and internal secretion of cholesterol. It was first demonstrated that a significant positive linear correlation exists between individual values of cholesterolemia and those of internal secretion of cholesterol. Secondly, using [14C]acetate as the cholesterol precursor it was shown that ingestion of the cystine-enriched diet increased hepatic but not intestinal cholesterogenesis. Individual values of cholesterolemia were linearly correlated to those of [14C]acetate incorporation into the hepatic sterols. Results obtained by this method were validated by determining the 13C-labeling pattern of cholesterol synthesized de novo by the liver and the intestine after [13C]acetate infusion. Indeed, this labelling indicated that the dilution of exogenous acetyl-CoA in the liver was not changed by cystine feeding, whereas that in the intestine was enhanced. It is concluded that the plasma cholesterol level varies with internal cholesterol secretion, depending on the organ which determines the variations of this secretion: it decreases when intestinal cholesterogenesis increases, whereas it increases when hepatic cholesterogenesis increases. Finally, the use of [14C]acetate coupled with lipoprotein analysis in rats fed the cystine-enriched diet, in control rats and in rats fed a cholesterol-enriched diet, allowed a new linear correlation to be demonstrated: between cholesterol concentration in LDL2 (lipoproteins of density 1.040-1.063 g/ml) and [14C]acetate incorporation into liver sterols. Our results suggest that LDL2 are produced by the liver in relation to cholesterogenesis in this organ.

Plasma and lipoprotein cholesterol in rats fed L-amino acid-supplemented diets.

The effect of feeding amino acid-supplemented diets on plasma cholesterol concentration and distribution in the lipoproteins was studied on adult rats. A control diet (without any amino acid addition), and experimental diets supplemented with one of the following L-amino acids: lysine (10%), cystine (5%), methionine (1%), tryptophan (10%), valine (5%), and histidine (5%), were given for 2-4 months. Rats fed the lysine-, cystine- and tryptophan-added diets exhibited constant weights throughout the experiment, whereas those fed the other amino acid-added diets showed body weight gains quite similar to control rats. Two amino acids were shown to lower plasma cholesterol concentration: lysine (by 30%) and tryptophan (by 35%); one amino acid increased it: cystine (by 46%). The cholesterol distribution in the lipoproteins was significantly modified, principally when rats ingested cystine-enriched diets: as compared to control rats, the cholesterol concentration in lipoproteins of density between 1.040 and 1.063, and in high density lipoproteins (HDL), was increased by 174 and 58%, respectively.

Effects of excess dietary L-cystine on the rat plasma lipoproteins.

The effects of excess dietary cystine on the cholesterol and protein contents of rat plasma lipoproteins are described. 5% L-cystine was added to a semisynthetic diet containing 23% casein and 0.05% cholesterol, to the same diet enriched with 1% cholesterol or containing tristearin instead of lard. Rats were fed the diets during 2 months. The addition of cystine led to an increase in the plasma cholesterol level of the rats fed with the basal diet (from 0.92 to 1.56 mg/ml). But it produced a reduction of this level in cholesterol-fed rats (from 1.71 to 1.49 mg/ml). These different changes in the total plasma cholesterol level are explained by the specific effects of cystine on each lipoprotein: whatever the diet, cystine supplementation reduced the chylomicron and VLDL cholesterol contents and increased that of LDL (especially LDL2: density 1.040-1.063) and HDL. This study allowed us to compare 2 conditions which lead to hypercholesterolemia but which have opposite effects on hepatic cholesterogenesis: the supplementation of the same basal diet with 1% cholesterol or 5% cystine. In cholesterol-fed rats, the major part (49%) of plasma cholesterol was found in the chylomicrons and VLDL while the LDL2 cholesterol content was low (0.07 mg/ml plasma). Conversely, cystine-fed rats had a low chylomicron and VLDL plasma content (both enriched in apoprotein E), whereas up to 33% of the plasma cholesterol were carried by LDL2. Thus the production of LDL2 in cholesterol and cystine-fed rats could be related to hepatic cholesterogenesis.