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PubMed1983

Experimental production of rabbit mucoid enteritis.

Rabbit mucoid enteritis (mucoid enteropathy) is a subacute fatal disease of weanling rabbits with unknown cause. Mucoid enteritis was experimentally produced by ligating the large intestines in rabbits. Of the rabbits with ligated cecum and those with ligated colon, 70% and 45%, respectively, had excessive production of mucus and passed large amounts of mucus with feces, closely resembling the naturally occurring mucoid enteritis. Injection of oxytetracycline into the cecum at the time of ligation prevented the development of mucoid enteritis, and injection of cholestyramine markedly reduced the frequency of the disease in the rabbits with ligated cecum.

Animals↗

PubMed1978

Characterization of the microsomal steroid-8-ene isomerase of cholesterol biosynthesis.

Rat liver microsomes contain an enzyme that catalyzes the isomerization of the nuclear double bond of steroids from the 8(9) position to the 7(8) position. The enzyme is most active with zymosterol, 5alpha-cholesta-8,24-dien-3beta-ol, which is a precursor of cholesterol. Properties of the microsomal isomerase have now been studied, and preliminary data are reported on both regulation of enzymic activity and first steps in the solubilization of the enzyme from membranes. After a brief lag period, the velocity of isomerase is relatively constant for about 5 min of incubation, and then isomerization subsides. The apparent Michaelis constant (52-70 micro M) is difficult to determine accurately, due to these complex kinetic changes. V(max) is 4.0-4.7 nmol/min per mg of microsomal protein. The apparent specific activity is more than ten times that of liver microsomal methyl sterol oxidase. The maximal specific activity of microsomal isomerase is approximately doubled when rats are fed an intestinal bile acid sequestrant, cholestyramine. Changes in specific activity of isomerase parallel changes in activities of other microsomal enzymes of cholesterol biosynthesis, such as 3-hydroxy-3-methylglutaryl-CoA reductase and 4-methyl sterol oxidase. Isomerase activity is destroyed by phospholipase A digestion, high concentration of bile salts, and solvent extraction, all of which are known either to remove phospholipid or to alter microsomal membrane integrity. On the other hand, isomerase remains active in the presence of a mild, nonionic detergent, Triton WR-1339; thus, solubilization with nonionic detergents is under study.

Animals↗

PubMed1984

The regulation of acetoacetyl-CoA synthetase activity by modulators of cholesterol synthesis in vivo and the utilization of acetoacetate for cholesterogenesis.

[3-14C]Acetoacetate, injected subcutaneously into rats, was rapidly incorporated into hepatic cholesterol and fatty acids. Injection of radiolabeled acetoacetate, acetate, or glucose resulted in the preferential incorporation of acetoacetate into cholesterol. The postmitochondrial supernatant of a rat liver homogenate has the capacity to synthesize radiolabeled sterols from [3-14C]acetoacetate, and this capacity surpasses its capacity to utilize [1-14C]acetate. The activity of acetoacetyl-CoA synthetase, a cytoplasmic enzyme that activates acetoacetate, was found to be highly regulated by modulators known to affect the activity of 3-hydroxy-3-methylglutaryl-CoA reductase and/or cholesterol biosynthesis in liver and adrenals of adult rats. Acetoacetyl-CoA synthetase activity was depressed by feeding cholesterol or mevalonate administration and was enhanced by the addition to the diet of mevinolin and/or cholestyramine. The activity of acetoacetyl-CoA synthetase in adrenals was enhanced by treatment of the animals with 4-aminopyrazolopyrimidine. These changes in activity of acetoacetyl-CoA synthetase were in synchrony with changes in the activities of 3-hydroxy-3-methylglutaryl-CoA synthase and 3-hydroxy-3-methylglutaryl-CoA reductase. The evidence suggests that the regulation of acetoacetyl-CoA synthetase activity and the utilization of acetoacetate for lipogenesis is closely linked to the regulation of cholesterogenesis.

Acetoacetates↗

PubMed1984

Diurnal variation of cytosolic fatty acid-binding protein content and of palmitate oxidation in rat liver and heart.

Delipidated proteins from albumin-free liver and heart cytosol obtained from rats sacrificed at the mid-dark or the mid-light phase of the light cycle were assayed for their palmitate-binding capacity. In both tissues a marked variation of this binding capacity was observed from about 3-4 nmol/mg of protein in the mid-light phase of the cycle to about 7-8 nmol/mg of protein in the mid-dark phase. Sephadex G-75 chromatography of the cytosolic proteins revealed that the palmitate binding could in all cases almost entirely be attributed to proteins of Mr = 12,000-14,000, suggesting that the observed diurnal variations are related to differences in the content of fatty acid-binding protein (FABP). In both rat liver and heart FABP represents about 4 (mid-light) to 8% (mid-dark) of the total soluble proteins. Cholestyramine feeding increased the FABP content of liver cytosol from rats sacrificed at the mid-light phase, but not in those sacrificed at the mid-dark phase, in such a way that the diurnal variation of the FABP content virtually disappeared. The palmitate oxidation capacity and citrate synthase activity also exhibited a concomitant diurnal periodicity in rat liver and, to a lesser extent, in rat heart. The results provide additional evidence for an important role of FABP in cellular fatty acid metabolism in both liver and heart and for the similarity of FABP with sterol carrier protein.

Animals↗

PubMed1984

A role for milk phospholipids in protection against gastric acid. Studies in adult and suckling rats.

Animal milk was tested directly for antiulcer activity in a rat model system. The severe mucosal necrosis and intragastric bleeding induced by the luminal administration of supraphysiologic 0.6 N HCl was significantly reduced (50%-70%) if both suckling rats and adults were pretreated per os with raw rat or bovine milk. Pasteurized/homogenized bovine milk also gave protection, although to a lesser extent (30%-50% reduction in bleeding). Treatment of milk with cholestyramine removed 50%-80% of the surface-active phospholipids from milk and also eliminated milk's protective property, an effect that was reversed upon addition of phospholipids to the extracted milk. The antiulcer action of milk in rats could be related to its concentration of dipalmitoyl lecithin. These findings suggest that milk has a potent antiulcer activity that may be attributable to its phospholipid constituents.

Animals↗

PubMed1983

Relationship between metabolism and composition of low density lipoproteins in rabbits on semi-purified diet.

The metabolism of 125I-labelled apoprotein of low density lipoproteins was studied in rabbits fed either commercial or semi-purified, cholesterol-free, diet. The rise in apo-LDL intravascular pool size observed in the semi-purified group is accompanied by a marked decrease in the fractional catabolic rate and an increase in the total catabolic rate. The semi-purified diet induces an increase in the cholesterol ester/triglyceride ratio of the LDL which is normalized by cholestyramine therapy. The concomitant alterations in both LDL metabolism and lipid composition raise the possibility that enrichment of LDL in cholesterol esters is a consequence of the delayed LDL clearance from the plasma.

Animals↗

PubMed1982

Antacids and bile salts.

Antacids, especially aluminium hydroxide, adsorb bile salts and lysolecithin with an affinity and capacity comparable to that of cholestyramine, a property which is likely to contribute to the beneficial effect of antacids in peptic ulceration. Dihydroxy bile salts are bound more strongly than trihydroxy bile salts and glycine conjugates more strongly than taurine conjugates, but ambient pH does not seem to have any effect on the binding. The bile salt-binding property of aluminium hydroxide may be of therapeutic value in the management of bile salt-induced diarrhoea, but its usefulness in the management of bile-reflux gastritis still remains questionable.

Adsorption↗

PubMed1980

Properties of purified rat hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase and regulation of enzyme activity.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase from rat liver microsomes has been purified to apparent homogeneity with recoveries of approximately 50%. The enzyme obtained from rats fed a diet supplemented with cholestyramine had specific activities of approximately 21,500 nmol of NADPH oxidized/min/mg of protein. After amino acid analysis a specific activity of 31,000 nmol of NADPH oxidized/min/mg of amino acyl mass was obtained. The s20,w for HMG-CoA reductase was 6.14 S and the Stokes radius was .39 nm. The molecular weight of the enzyme was 104,000 and the enzyme subunit after sodium dodecyl sulfate-polyacrylamide gel electrophoresis was 52,000. Antibodies prepared against the homogeneous enzyme specifically precipitated HMG-CoA reductase from crude and pure fractions of the enzyme. Incubation of rat hepatocytes for 3 h in the presence of lecithin dispersions, compactin, or rat serum resulted in significant increases in the specific activity of the microsomal bound reductase. Immunotitrations indicated that in all cases these increases were associated with an activated form of the reductase. However activation of the enzyme accounted for only a small percentage of the total increase in enzyme activity; the vast majority of the increase was apparently due to an increase in the number of enzyme molecules. In contrast, when hepatocytes were incubated with mevalonolactone the lower enzyme activity which resulted was primarily due to inactivation of the enzyme with little change in the number of enzyme molecules. Immunotitrations of microsomes obtained from rats killed at the nadir or peak of the diurnal rhythm of 3-hydroxy-3-methylglutaryl-CoA reductase indicated that the rhythm results both from enzyme activation and an increased number of reductase molecules.

Amino Acids↗

PubMed1983

Alteration of the degree of biliary cholesterol saturation in the hamster and rat by manipulation of the pools of preformed and newly synthesized cholesterol.

Our studies compared the effects of changing the availability of newly synthesized and preformed cholesterol by various dietary manipulations on biliary cholesterol secretion in the hamster and rat. In hamsters fed a plain pelleted diet, only 2%-5% of biliary cholesterol was derived directly from newly synthesized sterol. Cholestyramine feeding, through a stimulation of hepatic sterol synthesis, increased this fraction fivefold but did not change total biliary cholesterol output. The relative cholesterol content increased significantly due to a reduction in bile acid and phospholipid output. In contrast, biliary cholesterol output was increased several-fold in hamsters fed a fat-free diet. These animals also manifested a pronounced increase in whole-body sterol synthesis, this being due principally to an increase in hepatic sterol synthesis. Although this resulted in the transport of much more newly synthesized cholesterol directly into bile, this did not account for the disproportionately high rate of biliary cholesterol output. Such excess sterol was derived predominantly from a preformed source. Unlike hamsters, rats fed the fat-free diet manifested a marked reduction in hepatic and whole-body sterol synthesis, bile acid pool size, and bile acid and cholesterol output in bile. These studies demonstrate that when hepatic cholesterol synthesis increases in response to a need for more sterol in the body, a greater proportion of biliary cholesterol is derived directly from newly synthesized sterol, but total biliary cholesterol output is unchanged. In contrast, when more cholesterol is synthesized than is needed to maintain cholesterol balance, biliary cholesterol output may increase. Such excess biliary sterol is derived predominantly from a preformed source rather than from the transport of newly synthesized sterol directly across the canalicular membrane.

Animals↗

PubMed1982

Studies of arterial wall glycosaminoglycans and collagen during experimental regression of atherosclerotic lesions in cynomolgus monkeys.

The effect of various antiatherogenic regimens on glycosaminoglycan and collagen concentrations in aortas from cynomolgus monkeys with diet-induced atherosclerosis was studied. The drugs and materials that were studied included d-thyroxine, [4-chloro-6-(2,3-xylidino)-2-pyrimidinyl]thioacetic acid, cholestyramine, alfalfa, and glucophage. The treatments resulted in varied degrees of regression of lesions. The mean hydroxyproline concentration in aortas among groups of animals treated with different regimens was significantly different within the groups (p less than 0.001) and correlated with the severity of the lesions (p less than 0.01). The mean total glycosaminoglycan concentration among different groups did not differ significantly but correlated positively (p less than 0.05) with the severity of lesions. Heparan sulfate and hyaluronic acid increased with regression and decreased with increasing severity of lesions, whereas chondroitin sulfates followed an opposite trend. These observations show connective tissue components are intimately involved in remodeling the aorta during regression of diet-induced atherosclerosis.

Animals↗

PubMed1982

[Diagnosis, clinical features and treatment of hyperlipidemias in children].

Hyperlipidemias represent one of the most important risk factors for the development of premature atherosclerotic disease. If prevention of ischaemic cardiovascular disease, which is responsible for about 50% of the deaths in Western Europe, should be successful, diagnosis and treatment of hyperlipidemic states should start as early as possible. A short overview concerning the composition and the metabolism of the lipoproteins is given and theoretical and practical aspects for the classification of the different forms of hyperlipoproteinemia during childhood are pointed out. Laboratory determinations are described and therapeutic approaches of the main pediatric hyperlipidemias are given: polygenetic and combined familial hyperlipidemias should be treated by diet alone, whereas familial hypercholesterolemias request drug treatment: cholestyramine, given in doses between 4 and 8 g seems to be the drug of choice. Possible future aspects of drug treatment are discussed, even those who are shown to increase the number of LDL-receptors, which are blocked in that disease. Finally, efforts are emphasized to screen all children of families, in which premature heart disease or hypercholesterolemia occur.

Adolescent↗

PubMed1980

Diurnal variation of LDL and HDL cholesterol.

Determination of a 24-hour lipoprotein lipid profile on a mixed diet showed a typical increase in VLDL (includes chylomicrons) lipids following food intake in normal subjects. The change was less marked or absent in patients with jejuno-ileal by-pass and after cholestyramine treatment of a case with post-ileal-resection diarrhoea. Triglycerides of other lipoproteins did not fluctuate very much but free and esterified cholesterol of LDL and HDL showed a significant diurnal variation: lowest values were seen early in the morning followed by an increase before breakfast, with the highest levels during the afternoon in most cases. No clearcut precursor-product relationship could be seen between VLDL and LDL or HDL, yet the rhythmic changes in the VLDL levels and/or in cholesterol synthesis may be causally associated with the diurnal variation of cholesterol in LDL and HDL.

Adolescent↗

PubMed1980

Combined drug therapy for familial hypercholesterolemia.

Six familial hypercholesterolemic subjects were treated with a combination of cholestyramine (16 g/day) and nicotinic acid (3 g/day). This therapy consistently lowered plasma cholesterol and triglyceride by, on average, 41% and 37% respectively. Very low density and low density lipoprotein cholesterol fell, while high density lipoprotein cholesterol rose significantly. Plasma apolipoprotein levels were also affected by treatment. Apolipoprotein A-I rose 26% and apolipoprotein B fell 31%. In addition, there was a fourfold increase in plasma high density lipoprotein subfraction2 (HDL2), although HDL3 remained unaltered. These favorable changes in a number of atherosclerotic risk indices commend the use of this drug combination in the treatment of heterozygous familial hypercholesterolemia.

Adult↗

PubMed1981

Regulation of bile acid synthesis. Measurement of cholesterol 7 alpha-hydroxylase activity in rat liver microsomal preparations in the absence of endogenous cholesterol.

A rapid procedure was developed to measure hepatic cholesterol 7 alpha-hydroxylase activity in the absence of endogenous microsomal cholesterol. This method involves the preparation of an acetone powder from the microsomal fraction of rat liver that retains its cholesterol 7 alpha-hydroxylase activity and contains virtually no endogenous cholesterol. The enzyme activity is measured in the presence of labeled exogenous cholesterol as the only substrate source, and can be expressed in terms of picomoles of product formed when a simple isotope incorporation procedure is employed. Optimal assay conditions were determined and the reproducibility of the acetone powder cholesterol 7 alpha-hydroxylase assay was established. A comparison of the proposed method with the previously used double isotope derivative procedure showed comparable enzyme activities in control rats and both methods exhibited an increase in the rate of hydroxylation after cholestyramine treatment and a decrease following cholic acid treatment. In contrast, the acetone powder assay did not show any change in cholesterol 7 alpha-hydroxylase activity during cholesterol feeding. These findings suggest that bile acid feeding influences the amount of active cholesterol 7 alpha-hydroxylase present in the liver whereas cholesterol feeding does not.

Animals↗

PubMed1981

Antibiotic-associated pseudomembranous colitis in children.

Ten cases of antibiotic-associated pseudomembranous colitis in children are reviewed. The ages ranged from 4 years to 17 years; the most frequently implicated antimicrobial agents were penicillins in six children and clindamycin in two. Stool assays showed specimens from all ten patients yielded a cytopathic toxin which was neutralized by Clostridium sordellii antitoxin with titers ranging from 1:40 to 1:40,000. Bacterial cultures of nine specimens uniformly yielded Clostridium difficile with a median concentration of 10(5.4) organisms per gram of wet weight. All nine isolates of C difficile showed a vitro production of a cytopathic toxin which was similar to or identical with that which was detected in the original stool specimen. All ten patients recovered. Six were treated with oral vancomycin and showed a good therapeutic response; one patient, however, suffered two relapses when treatment was discontinued, requiring a total of three courses of oral vancomycin. Two patients received cholestyramine and responded well. These observations provide supportive evidence that C difficile is responsible for antibiotic-associated pseudomembranous colitis in children and document efficacy of the newer therapeutic modalities in this patient population as well.

Administration, Oral↗

PubMed1981

Circadian variation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in swine liver and ileum.

The temporal variation of HMG-CoA reductase activity in the liver and intestine of swine was investigated. The thin-layer chromatographic method widely used in the assay of the reductase was successfully applied to the porcine enzymes. Parallel circadian rhythms were demonstrated in both hepatic and ileal reductases from mash-fed animals. Peak activity occurred approximately 6 hr after feeding, 2.7-fold over the basal level in the liver, and 1.6-fold in the ileum. A milk-cholesterol diet caused a marked depression of both rhythms (90% in liver, 50% in ileum); however, the hourly variation in activity persisted in both organs. Cholestyramine was found to elevate hepatic activity (2.7-fold throughout the rhythm) without affecting that of the intestine. Clofibrate had no effect on either enzyme at any time during the cycle despite a 34% reduction in serum cholesterol concentrations.

Animals↗

PubMed1981

In vivo regulation of canine intestinal 3-hydroxy-3-methylglutaryl coenzyme A reductase by cholesterol, lipoprotein, and fatty acids.

Thirty-Vella-isolated ileal segments in dogs were used to study the regulation of intestinal cholesterol synthesis. This excluded fistula enabled independent in vivo manipulation of luminal and vascular influences on mucosal cells. Segments were studied repeatedly and each animal served as its own control. Cholesterol synthesis rate was assessed by measuring mucosal activity of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Luminal cholesterol and 25-hydroxycholesterol were shown to reduce HMG CoA reductase activity to 64 +/- 7% and 42 +/- 4%, respectively, of control within 4 hr. Reductase activity in the excluded segment also responded to alterations in serum cholesterol produced by cholesterol or cholestyramine feeding. Similarly, in vitro studies showed that lipoprotein cholesterol inhibited HMG CoA reductase in mucosa from the excluded segment but not in mucosa from intact bowel. In contrast to sterols, fatty acids stimulated HMG CoA reductase activity by luminal contact. These findings suggest that the cholesterol needs of canine intestinal epithelial cells are acutely balanced by absorption and synthesis of cholesterol. Mucosal cells may also utilize lipoprotein cholesterol under certain conditions, perhaps via low density lipoprotein receptors. Fatty acid absorption stimulated cholesterol synthesis in the absence of luminal cholesterol, perhaps to facilitate chylomicron formation.

Animals↗

PubMed1981

Effect of three bile acid binding polymers on the biosynthesis of 14C-cholesterol from 14C-sodium acetate in the rat.

The relative activity of three bile acid binding polymers in increasing cholesterol biosynthesis in the rat from 14C-acetate was determined by measuring blood levels of 14C-cholesterol after intraperitoneally administered 14C-acetate. CAT-FLOC and 3,3-ionene were 4-5 times more active than cholestyramine in this study which correlated well with the results of hypocholesteremic testing in dogs.

Acetates↗