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PubMed1995

Cholesterol biosynthesis from lanosterol: regulation and purification of rat hepatic sterol 14-reductase.

We have previously characterized the membrane-bound sterol 14-reductase (14-reductase) that catalyzes anaerobically NADPH-dependent reduction of the 14-double bond of delta 8,14-diene or delta 7,14-diene sterols that are sterol intermediates in cholesterol biosynthesis in mammals (Paik et al. (1984) J. Biol. Chem. 259, 13413-13423). To elucidate the regulatory mechanism as well as molecular characteristics of the 14-reductase, we extended our investigation on the consequences of alteration of the enzymic activity under various physiological conditions. The enzymic activity of rat hepatic sterol 14-reductase was induced more than 11-fold by feeding 5% cholestyramine plus 0.1% lovastatin (the CL-diet) for 7 days but was severely suppressed by feeding 5% cholesterol or 0.01% AY-9944 (an inhibitor of 14-reductase) for the same period. The increase or decrease in the 14-reductase activity also parallels the same change in the cholesterol synthetic rate in hepatocytes from rats that had been fed either the CL-diet or 0.01% AY-9944. In vitro inhibition studies revealed that AY-9944 acts as a competitive inhibitor of the 14-reductase (Ki = 0.26 microM). A diurnal variation was observed for the 14-reductase with peak activity near the middle of the dark cycle (10 p.m.), which was abolished by administration of cycloheximide. With induced enzyme conditions 14-reductase has been further purified with chromatographic procedures to near homogeneity. Purified 14-reductase appears to be a M(r) = 70,000 protein that is composed of two equally-sized subunits having a M(r) = 38,000. All properties of the purified 14-reductase suggest that the solubilized enzyme is the principal 14-reductase of microsomes. Taken together, our results provide the first evidence in support of a previously unknown regulatory role for the 14-reductase in the overall cholesterol synthetic pathway.

Animals↗

PubMed1985

Inhibition of liver lipase in vivo leads to induction of de novo cholesterol synthesis in rat liver.

Rats were injected with control-gamma-globulins or anti-liverlipase. The anti-liverlipase treatment resulted in a 69-78% inhibition of the salt-resistant lipase activity (liver lipase) in the liver. De novo cholesterol synthesis was significantly higher in slices of livers from anti-liverlipase treated rats than from control-gamma-globulin injected rats. The anti-liverlipase treatment also affected all plasma lipoprotein fractions. If the rats had been fed a cholestyramine containing diet no effect of anti-liverlipase on cholesterol synthesis was found. In these rats the effects on plasma lipoprotein fractions were more pronounced than in the control fed rats.

Animals↗

PubMed1988

Feeding of lovastatin to rats increases the activity of the hepatic mitochondrial outer carnitine palmitoyltransferase.

Administration of lovastatin to male, Sprague-Dawley rats by addition of the drug to the normal chow diet caused a two-fold increase in the activity of the hepatic mitochondrial outer carnitine palmitoyltransferase, but lovastatin apparently did not affect the sensitivity of the outer carnitine palmitoyltransferase to inhibition by malonyl-CoA. There was also no effect of lovastatin on the activity of the hepatic mitochondrial inner carnitine palmitoyltransferase. Feeding of cholestyramine to rats did not affect either the mitochondrial outer carnitine palmitoyltransferase or the mitochondrial inner carnitine palmitoyltransferase.

Acyltransferases↗

PubMed1991

Modification of the radiochemical assay of rat liver mevalonate-5-diphosphate decarboxylase and induction and stabilization of the activity.

Problems encountered in attempts to purify mevalonate-5-diphosphate decarboxylase from rat liver are addressed. These are the quantitative, facile separation of [14C]isopentenol in the radiochemical assay (2) the instability of the enzyme activity and (3) the very low activity in rat liver. The assay was modified by using Sep Pac C18 filters to bind and release [14C]isopentenol. Authentic isopentenol was quantitated by absorbance at 210 nm wavelength and the extinction coefficient estimated to be epsilon m = 3.26 X 10(3). Recovery of authentic isopentenol from aqueous solution after binding and elution into methanol was quantitative from 10-100 nmols. Recovery of [14C]ispentenol from assay mixtures using 2-[14C]mevalonate-5-diphosphate and alkaline phosphatase to hydrolyze phosphate was quantitative using Sep Pac filter but not using petroleum ether extraction. Enzyme activity was stabilized by phenylmethylsulfonyl fluoride, aprotinin and leupeptin and was stable at -73 degrees C for 3 months. Activity of the decarboxylase was increased by 5-fold after feeding young rats 2.5% cholestyramine for ten days to four weeks.

Animals↗

PubMed1982

The role of cholesterol 7 alpha-hydroxylase in the hypobetalipoproteinaemic activity of SKF-525A in rats.

Administration of SKF-525A to rats fed on a stock diet specifically decreased the serum concentration of low-density lipoprotein. SKF-525A and cholestryamine also reversed the rise in circulating concentration of both very-low density and low-density lipoprotein that was observed in rats given a sucrose-based, cholesterol-supplemented diet. The enhancement of hepatic cholesterol 7 alpha-hydroxylase by SKF-525A or by cholestyramine is accompanied by homeostatic responses by the liver which include induction of low-density lipoprotein clearance and increased cholesterogenesis to attempt to replenish sterol pools. These compensatory mechanisms are separately controlled.

Animals↗

PubMed1987

Changes in hepatic dolichol and dolichyl monophosphate caused by treatment of rats with inducers of the endoplasmic reticulum and peroxisomes and during ontogeny.

Rats were treated with various inducers of the endoplasmic reticulum and peroxisomes and the properties and distributions of dolichol and dolichyl phosphate analyzed. The treatment of rats with carcinogenic agents 2-acetylaminofluorene, N-nitrosodiethylamine and 3-methylcholanthrene and with the compounds such as phenobarbital, terpentine, cholestyramine and di(2-ethylhexyl)phthalate have all caused changes in the microsomal or lysosomal contents of dolichol to various extents, but only the latter group influenced dolichyl-P concentration. Shortly after birth, the hepatic content of dolichyl-P reaches the adult level, whereas the level of the free alcohol is low at birth but increases continuously thereafter. Incorporation of [3H]mevalonate into dolichol was also dependent on factors other than de novo synthesis, e.g., the pool size. Rates of glycosylation reactions dependent on dolichyl-P exhibit considerable changes but are independent of the existing levels of lipid intermediate. GDP-mannosyl transferase activity increases greatly with birth, but the enzyme activity returns to the adult level within a day after birth. These results demonstrate that structural and functional modifications induced with drugs can greatly influence the content and distribution of dolichol which are independent of the existing levels of dolichyl-P.

2-Acetylaminofluorene↗

PubMed1990

The effects of inducers of the endoplasmic reticulum, peroxisomes and mitochondria on the amounts and synthesis of ubiquinone in rat liver subcellular membranes.

Rats were treated with inducers of peroxisomes, mitochondria and the endoplasmic reticulum, as well as receiving diets and drug known to influence the mevalonate pathway. Treatment with clofibrate and 2-diethylhexylphthalate (DEHP) increased microsomal and mitochondrial ubiquinone contents, but a decrease was observed in lysosomes. In vivo labeling of this lipid with [3H]mevalonate was also elevated. The amount of cholesterol did not change upon exposure to these inducers of peroxisomes and mitochondria, but its rate of labeling was decreased. The concentration of dolichol increased only after treatment with DEHP and only in lysosomes. The inducers of the endoplasmic reticulum phenobarbital, 3-methylcholanthrene and N-nitrosodiethylamine enhanced the rate of ubiquinone synthesis and exposure to the latter two substances also elevated the amount of this lipid in microsomes. A cholesterol-rich diet increased the labeling of ubiquinone and decreased cholesterol labeling, while cholestyramine treatment had opposite effects on lipid labeling in both microsomes and mitochondria. The results demonstrate that the ubiquinone contents of the various membranes of hepatocytes change in a characteristic manner under the influence of inducers and dietary factors. Clearly, the level of ubiquinone and its biosynthesis are regulated separately from those of the other products of the mevalonate pathway, cholesterol and dolichol.

Animals↗

PubMed1986

Detection of carriers of cerebrotendinous xanthomatosis.

Patients suffering from cerebrotendinous xanthomatosis (an autosomal recessive inborn error of metabolism) can easily be distinguished from patients not suffering from this disease, as the first excrete large amounts of the bile alcohol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol, in urine, whereas the second do not. In order to find out, whether carriers of cerebrotendinous xanthomatosis can be detected in a biochemical way, we compared known carriers with controls. The urinary excretions of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol of both groups were practically absent and no selection of carriers with cerebrotendinous xanthomatosis could be made on that basis. When, however, carriers and non-carriers were subjected to cholestyramine treatment, by which endogenous bile acid synthesis was stimulated, the urinary excretion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol in the carrier rose considerably, whereas this excretion remained essentially the same in the non-carriers. This test can be of value in the genetic counseling of carriers with cerebrotendinous xanthomatosis and helpful in the detection of newborn patients with cerebrotendinous xanthomatosis.

Adolescent↗

PubMed1988

Steinernema feltiae (= Neoaplectana carpocapsae): effect of sterols and hypolipidemic agents on development.

The structure and concentration of sterol in a lipid-defined artificial medium affected the development of the entomogenous nematode, Steinernema feltiae (= Neoaplectana carpocapsae). The nematode grew normally in vitro when the medium was supplemented with delta 5-desalkylsterol (cholesterol) or delta 5-desalkylsteryl ester (cholesterol oleate). The minimum amount of cholesterol in the medium that was necessary to support the development of S. feltiae to the climax population (i.e., dauer stage) was 0.0025%. The nematode also completed its life cycle normally when delta 0- or delta 7-desalkylsterols (cholestanol and lathosterol) were substituted for cholesterol. In contrast, development was inhibited when the medium contained delta 5,7-desalkylsterol (7-dehydrocholesterol); however, the nematode population reached the climax stage, in medium containing this sterol, when cholesterol was also present. S. feltiae was able to utilize delta 5- and delta 0-24 alpha-ethylsterols (sitosterol and sitostanol) as dietary sterols; however, when a delta 22-bond was introduced into the side chain (stigmasterol) the rate of development of the nematode slowed significantly. The growth of the nematode was also retarded when the medium contained delta 5,7,22-24 beta-methylsterol (ergosterol). The nematode population reached the climax stage in medium containing delta 8,24-4,14 alpha-trimethylsterol (lanosterol) only when cholesterol was also present. When S. feltiae was exposed to certain hypolipidemic agents, which are known to lower the level of lipids in human plasma (clofibrate, cholestyramine resin, niacin, and D-thyroxine), all but D-thyroxine affected the growth and development of the nematode in vivo (in Heliothis zea) and/or in vitro. Therefore further studies are warranted to determine how these drugs affect the lipid biochemistry of this nematode.

Animals↗

PubMed1991

Purification and characterization of 3-hydroxymethylglutaryl-coenzyme A reductase of Schistosoma mansoni: regulation of parasite enzyme activity differs from mammalian host.

The enzyme 3-hydroxymethylglutaryl-CoA (HMG-CoA) reductase plays a critical role in regulating the production of cholesterol, dolichols, and ubiquinones in mammals. The inhibition of this enzyme in Schistosoma mansoni is accompanied by a cessation of egg production by the female parasite and a reduced ability of the parasite to properly glycoslyate their proteins. Furthermore, we recently demonstrated that mevinolin, if given continuously over a period of 10-14 days, is a potent antischistosomal drug. In this paper, we describe the properties of purified HMG-CoA reductase from S. mansoni. Using affinity chromatography, we were able to obtain a 417-fold purification of the enzyme which had Km values similar to the rat enzyme for HMG-CoA and NADPH. The Ki value for mevinolin, a potent and selective inhibitor of the rat reductase (Ki = 0.6 nM), was significantly higher (Ki = 46 nM) for the schistosome enzyme. SDS-PAGE and HPLC of the purified enzyme resulted in the appearance of a single protein, which had a molecular weight (66,000) in the range reported for the rat enzyme. Parasite reductase activity, unlike that of its host, did not display a circadian rhythm. Furthermore, agents which elevate (cholestyramine) or decrease (cholesterol) mammalian reductase activity had no effect on the parasite enzyme. Our results suggest that the mechanism which regulates production of the parasite's enzyme may differ from its mammalian host.

Acyl Coenzyme A↗

PubMed1988

Levels of 7 alpha-hydroxy-4-cholesten-3-one in plasma reflect rates of bile acid synthesis in man.

A method for analysis of 7 alpha-hydroxy-4-cholesten-3-one in plasma is described. Following solid-phase extraction/purification the compound is determined by high-performance liquid chromatography using a UV detector. The median concentration in healthy subjects was 12 ng/ml (range 3-40). The levels were lower in diseases associated with a low bile acid production: extrahepatic cholestasis, less than 1.5 ng/ml (range less than 0.9-3); liver cirrhosis less than 1.5 ng/ml (range less than 0.9-38), and higher in diseases associated with a high bile acid production: cholestyramine treatment, 188 ng/ml (range 54-477); ileal resection 397 ng/ml (range 128-750). The levels were essentially normal in patients with colon resection. The results are consistent with a strong positive correlation between the levels of 7 alpha-hydroxy-4-cholesten-3-one in plasma and the rate of bile acid synthesis.

Adult↗

PubMed1990

Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea.

Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients.

Adult↗

PubMed1980

The bile acid binding and hypocholesterolemic action of two water-soluble polymers.

The in vitro bile acid binding properties of 2 water-soluble, linear, cationic resins, poly-[(dimethylimino)trimethylene chloride] or 3,3-ione C1, and poly-diallyldimethylammonium chloride) or CAT-FLOC were determined. Both polymers were substantially more active than cholestyramine. All were compared for hypocholesterolemic effect in normo-cholesterolemic dogs. CAT-FLOC and 3,3-ionene C1, administered at 1.8 and 1.2 g/day, respectively, exhibited cholesterol-lowering action equivalent to cholesteryramine given at 12 g/day. The results of this study suggest that effective reduction of plasma cholesterol may be achieved with significantly lower doses of bile acid sequestrants.

Animals↗

PubMed1980

The effect of compactin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, on cholesterogenesis and serum cholesterol levels in rats and chicks.

Compactin, [7-(1,2,6,7,8,8a-hexahydro-2-methyl-8-(2-methylbutyrylox)naphthyl)-3-hydroxyheptan-5-olide], a potent competitive inhibitor of the rate-determining step in cholesterol biosynthesis, was used to study the influence of changes in cholesterogenesis on serum cholesterol levels. Up to 3 h after a single oral dose (20 or 50 mg/kg) or after the last of a series of daily oral doses (50 mg/kg for 7 or 28 days) to young, male normolipidaemic rats, compactin consistently inhibited cholesterogenesis measured using 3H20 in liver, ileum and other extrahepatic tissues without affecting fatty acid synthesis. Compactin did not reduce serum or tissue cholesterol nor affect the serum concentration of other lipids nor the ratio between lipoprotein classes. A diurnal variation in the effect of compactin on cholesterogenesis was observed. For example, by 12--20 h after dosing, cholesterogenesis at all sites was increased above the comparable control value, indicating the induction of enzyme synthesis and overall there was little effect on the mass of cholesterol synthesized per day. Similar results were obtained using male chicks. Inhibition of cholesterogenesis by compactin was also observed in cholestyramine-treated rats, in which cholesterol turnover was markedly increased, and even in cholesterol-fed rats, in which cholesterogenesis already was repressed. In neither case, however, was inhibition of cholesterogenesis accompanied by a hypocholesterolaemic effect. It is concluded that a more persistent suppression of cholesterogenesis, than that observed with compactin in the rat, may be required in order to affect serum cholesterol concentrations.

Animals↗

PubMed1983

Experimental models of atherosclerosis regression.

Regression of atherosclerosis has been demonstrated in several species of animals, including rabbits, chickens, rats, dogs, pigeons, pigs, and nonhuman primates. Regression has been associated with withdrawal of cholesterol from the diet or with the ingestion of cholestyramine, alfalfa meal, or alfalfa saponins in monkeys fed high-cholesterol diets. Although regression of atherosclerosis has been documented by sequential contrast arteriography in humans, the correspondence of regression in animals and in humans needs to be established.

Animals↗

PubMed1991

Response to cholesterol-lowering drugs in familial defective apolipoprotein B-100.

The effect of cholestyramine and simvastatin, given separately or in combination, on serum lipid concentrations in 11 patients with heterozygous familial defective apolipoprotein B-100 was compared with that in 11 matched patients with heterozygous familial hypercholesterolaemia. In both groups of patients there was a substantial fall in serum lipid levels in response to treatment. There were no significant differences between the reductions in serum total or low-density lipoprotein cholesterol levels in the two groups.

Adult↗

PubMed1994

Effect of the acyl-CoA:cholesterol acyltransferase inhibitor, E5324, on experimental atherosclerosis in rabbits.

E5324, n-butyl-N'-[2-[3-(5-ethyl-4-phenyl-1H-imidazol-1-yl)propoxy]-6- methylphenyl]urea, a novel and orally absorbable acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated for its antiatherosclerotic and antihyperlipidemic effects in cholesterol-fed hypercholesterolemic rabbits. When administered concurrently with a high-cholesterol (0.5% cholesterol) diet for 12 weeks, E5324 (0.0025%, 0.005% and 0.01% in diet) lowered plasma total cholesterol levels dose-dependently (by about 55%-87% at the end of the experiment compared with the control) and also reduced atherosclerotic plaque formation (about 90% reduction at the highest dose; P < 0.01). In pre-established hypercholesterolemic rabbits, which had been pre-fed a high-cholesterol diet for 8 weeks, E5324 administered in the same diet at a dose of 0.005%, 0.01% or 0.02% for 4 weeks significantly reduced plasma cholesterol levels dose-dependently. Cholesterol content and ACAT activity in the aortic arch were also decreased (by about 72% and 58% at the highest dose, respectively) compared with the control. Another ACAT inhibitor, CI-976, had a similar action, but cholestyramine and probucol (2% and 1% in diet, respectively) lacked anti-atherosclerotic activity in this model. Furthermore, when pre-established hypercholesterolemic rabbits were fed normal rabbit chow diet with or without 0.02% E5324 for 4 weeks, changes in plasma cholesterol levels were similar in both E5324-treated and control groups. On the other hand, E5324 significantly reduced cholesterol content and ACAT activity in the aortic arch (by about 52% and 50%, respectively) compared with the control group. These results indicate that E5324 not only has hypocholesterolemic activity, but also may have a direct effect on the arterial wall in experimental atherosclerosis.

Anilides↗

PubMed1995

Intima-media thickness after cholesterol lowering in familial hypercholesterolemia. A three-year ultrasound study of common carotid and femoral arteries.

Patients with familial hypercholesterolemia (FH) (n = 53) were examined with B-mode ultrasound before and after 3 years of cholesterol-lowering therapy with pravastatin, cholestyramine, or a combination. The aim was to measure the progression rate of intima-media thickening during follow-up in the common carotid and common femoral arteries. Since for ethical reasons it was not possible to perform a randomized placebo controlled study in patients with FH, we chose to recruit an untreated control group with lower risk, matched for sex, age, height and weight, and with serum cholesterol below 6.5 mmol/l. At baseline, intima-media thickness was larger in the hypercholesterolemic group than in the control group in both the common carotid and common femoral arteries. The difference between the change over 3 years observed in the control group and the change observed in the hypercholesterolemic group was calculated and defined as 'net difference'. There was a -32% net difference in low density lipoprotein (LDL) in the hypercholesterolemic group during follow-up. The ultrasound investigation showed a concomitant net difference of -0.06 mm in mean carotid intima-media thickness (95% confidence interval, -0.11 to -0.01 mm) and of -0.09 mm in maximum carotid intima-media thickness (P < 0.05, 95% confidence interval, -0.16 to -0.01 mm), with no net change in lumen diameter. No decrease was recorded in common femoral intima-medial thickness. Seventeen of the patients with FH had a positive history of myocardial infarction (MI) and this subgroup had a significantly larger decrease in mean carotid intima-media thickness during follow-up than the subgroup of patients with a negative history of MI (P < 0.01). In conclusion, the results showed a reduction in common carotid intima-media thickness after long-term cholesterol-lowering therapy in patients with FH. This finding may indicate a beneficial effect on atherosclerosis development in these patients.

Anticholesteremic Agents↗