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At least 19 recordsLinked to original sources

PubMed1987

Relationships between dietary cholesterol, cholesterol absorption, cholesterol synthesis, and plasma cholesterol in rhesus monkeys.

The relationships between the cholesterol content of the diet, plasma cholesterol concentration, cholesterol absorption, and cholesterol synthesis (measured indirectly by desmosterol suppression technique) are explored in groups of high- and low-responding rhesus monkeys fed diets containing 0.02, 0.15 and 0.75 mg cholesterol/kcal. The cholesterol content of the diet (expressed as mg/kcal) is positively correlated with plasma cholesterol concentration and is negatively correlated with percent cholesterol absorption in both groups. Also the cholesterol content of the diet is negatively correlated (r = -0.66) with cholesterol synthesis only in low-responders but not in high-responders. Similarly, the correlation between percent cholesterol absorption and cholesterol synthesis is significant in the low-responders (r = 0.82, P less than 0.01) but not in the high-responders (r = 0.12, P greater than 0.1). Further, a negative correlation (r = -0.61) is observed between cholesterol synthesis and plasma cholesterol concentration in the low-responders but in the high-responders, there is no relationship between the parameters. From these correlations we conclude that the higher cholesterol absorption in the high-responders than in the low-responders is one important mechanism responsible for the development of severe hypercholesterolemia in the high-responding monkeys fed cholesterol. The results also suggest that there might be a lower sensitivity in the feedback inhibition mechanism of cholesterol biosynthesis in the high-responding than in the low-responding rhesus monkeys.

Animals↗

PubMed1992

Secretion of lipoprotein cholesterol by perfused livers from rabbits hypo- or hyperresponsive to dietary cholesterol: greater dietary cholesterol-induced secretion in hyperresponsive rabbits.

In two inbred strains of rabbits with high or low response of plasma cholesterol to dietary cholesterol, secretion of lipoprotein cholesterol by perfused livers was determined. The perfused rabbit livers secreted cholesterol into the perfusate at essentially constant rates between 30 and 120 min of perfusion. Most of the secreted cholesterol resided in VLDL. Addition of cholesterol to the diet of the donor rabbits caused a higher cholesterol:triglyceride ratio of lipoproteins secreted by the perfused liver. Such a rise was also seen in the plasma lipoproteins of cholesterol-fed rabbits. Plasma and perfusate lipoproteins differed in that the former had a higher cholesterol:triglyceride ratio. Cholesterol feeding produced a higher output of lipoprotein cholesterol by the perfused liver, the increment being greater in hyper- than in hyporesponders. Cholesterol-fed hyperresponders had higher liver cholesterol concentrations than their hyporesponsive counterparts. There was a direct relationship between the rise of liver cholesterol concentrations and the rise of hepatic secretion of lipoprotein cholesterol; this relationship was identical for hypo- and hyperresponders. We conclude that the higher cholesterolemic response to cholesterol feeding in the hyperresponders, when compared with the hyporesponders, can be explained, at least partly, by a greater cholesterol-induced hepatic secretion of lipoprotein cholesterol.

Animals↗

PubMed1979

Regulation of biliary cholesterol output in the rat: dissociation from the rate of hepatic cholesterol synthesis, the size of the hepatic cholesteryl ester pool, and the hepatic uptake of chylomicron cholesterol.

These studies were designed to determine the importance of the rate of hepatic cholesterol synthesis, the size of the hepatic cholesteryl ester pool, the amount of chylomicron cholesterol reaching the liver, and the rate of bile acid transport into bile as determinants of the rate of biliary cholesterol output. Female rats that had been subjected to diurnal light cycling, fasting for 48 hr, intravenous administration of chylomicrons, and diets containing either cholestyramine, cholesterol, or bile acid underwent total biliary diversion for 2 hr. The animals were then killed and the rates of hepatic cholesterol synthesis and levels of hepatic esterified cholesterol were measured along with biliary lipid concentrations. Despite a 1000-fold variation in the rate of hepatic cholesterogenesis and a 100-fold variation in the levels of cholesteryl esters, the output and molar percentage of cholesterol in bile remained essentially constant with the exception of an approximate doubling in the output of cholesterol, as well as of bile acid and phospholipid in those animals fed bile acid. However, in this latter group the molar percentage of each component was unchanged. The administration of a bolus of chylomicrons did not alter output or molar percentage of cholesterol. Total biliary diversion for 36 hr and bile acid infusion were used to markedly vary the rate of biliary bile acid output. Cholesterol and phospholipid output remained tightly coupled to bile acid output over almost a 40-fold range. In other experiments it was shown that biliary cholesterol output could be driven by bile acid infusion to a similar extent in rats in which the rate of hepatic cholesterogenesis had been varied over a 26-fold range. It was concluded that the rate of hepatic cholesterol synthesis, the level of hepatic cholesteryl esters, and the amount of cholesterol absorbed from the diet play no role in determining the rate of biliary cholesterol secretion, at least in this species.-Turley, S. D., and J. M. Dietschy. Regulation of biliary cholesterol output in the rat: dissociation from the rate of hepatic cholesterol synthesis, the size of the hepatic cholesteryl ester pool, and the hepatic uptake of chylomicron cholesterol.

Animals↗

PubMed1987

Regulation of rat hepatic cholesterol metabolism. Effects of lipoprotein composition on acyl coenzyme A:cholesterol acyltransferase in vivo and in the perfused liver and on hepatic cholesterol secretion.

Lipoproteins that are removed from the circulation by the liver can deliver both cholesterol and triglycerides to the hepatocyte. Relative proportions of these lipids may vary in lipoproteins and, thus, their uptake may have differing effects on cholesterol homeostasis. To study this, lipoproteins containing the same amounts of cholesterol but different amounts of triglyceride were administered to intact rats or to an isolated perfused rat liver. The responses of acyl coenzyme A:cholesterol acyltransferase (ACAT), very low density lipoprotein (VLDL) triglyceride and cholesterol secretion, and biliary cholesterol content were examined after 2 hr. Administration of triglyceride-rich chylomicrons (average triglyceride:cholesterol = 136.5 by mass) in vivo or their remnants (average triglyceride:cholesterol = 32.7 by mass) to the perfused liver resulted in an 80% decrease in ACAT activity. In the perfused liver system, VLDL cholesterol and triglyceride secretion was increased while biliary cholesterol content decreased. Administration of standard chylomicrons (average triglyceride:cholesterol = 33.9 by mass) or their remnants (average triglyceride:cholesterol = 11.4 by mass) lowered ACAT activity by 24% in vivo, but had no significant effect on any of the parameters measured in the perfused liver system. Administration of cholesterol-rich VLDL (average triglyceride:cholesterol = 0.47 by mass) in vivo increased ACAT activity 1.4-fold, but administration of their remnants (average triglyceride:cholesterol = 0.17 by mass) had little effect on any of the parameters measured in the perfused liver. Thus, the lipid composition of lipoproteins removed by the liver elicited acute responses by parameters important in the maintenance of hepatic cholesterol homeostasis. These responses reflected the net effects of both the cholesterol and the triglyceride contents of the particles.

Acyl Coenzyme A↗

PubMed1991

Effects of perturbations in hepatic free and esterified cholesterol pools on bile acid synthesis, cholesterol 7 alpha-hydroxylase, HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase and cytosolic cholesteryl ester hydrolase.

Effects of expansion of the hepatic free cholesterol pool on bile acid and cholesterol metabolism and homeostasis were examined in rats fed cholesterol in high-fat diets or treated with oleyl-p-(n-decyl)-benzenesulfonate (ODS) or progesterone. Cholesterol feeding for 10-16 days, which increased free (33%) and esterified (6-fold) cholesterol, had no effect on cholate synthesis, total bile acid synthesis, or cholate turnover, whereas these activities were increased 60-80% by ODS and progesterone, which produced only small increases (19%) in free cholesterol. Cholesterol feeding reduced beta-hydroxy-beta-methylglutaryl (HMG)-CoA reductase (72%) and cholesteryl ester hydrolase (48%) and increased acyl-CoA:cholesterol acyltransferase (184%), whereas ODS and progesterone reversed these compensatory responses in cholesterol-fed rats. Cholesterol 7 alpha-hydroxylase was changed no more than 22% by any treatment. A bolus of ODS elevated biliary cholesterol output 41% and shifted biliary bile acid synthesis and composition toward 12-deoxy bile acids. These effects were not seen in ODS-fed or progesterone-treated rats, in which cholesteryl ester stores were depleted. It is concluded that effects of free cholesterol on bile acid synthesis and biliary cholesterol are probably mediated by specific precursor or regulatory pools which can be independently regulated and which represent a relatively small fraction of hepatic free cholesterol.

Animals↗

PubMed1989

Cholesterol absorption: regulation of cholesterol synthesis and elimination and within-population variations of serum cholesterol levels.

Obesity and dietary plant sterols were negatively associated with fractional absorption of dietary cholesterol in a random population of 63 middle-aged men. Absorbed dietary cholesterol increased linearly with the increase of dietary cholesterol intake. The higher the fractional and absolute absorption of dietary cholesterol the lower the rates of biliary secretion, fecal elimination, and cholesterol synthesis. The findings also revealed that high serum levels of total, LDL, and HDL cholesterol were associated with high cholesterol absorption and that of HDL cholesterol was associated also with low synthesis and fecal elimination of cholesterol. Thus, cholesterol absorption efficiency and absorbed dietary cholesterol significantly regulate cholesterol synthesis and elimination and are important determinants of within-population variation in the serum levels of total, LDL, and HDL cholesterol.

Absorption↗

PubMed1985

Amperometric assays of total and free cholesterols in serum by the combined use of immobilized cholesterol esterase and cholesterol oxidase reactors and peroxidase electrode in a flow injection system.

A flow injection system for assays of total cholesterol and free cholesterol was described. The total cholesterol assay system included an amperometric peroxidase electrode to measure hexacyanoferrate(III) converted from hydrogen peroxide, which was generated by injecting a 2-microliter sample into the packed-bed reactors of immobilized cholesterol esterase and cholesterol oxidase covalently bound to silica. The free cholesterol was assayed with the same system without the cholesterol esterase reactor. The peak current was linearly related to cholesterol in the range 2-160 mg/dl and to total cholesterol in the range 3-300 mg/dl; the assay speed was about 80 samples/h for free cholesterol and 40 samples/h for total cholesterol. Reliable results were obtained in the assays of free cholesterol and total cholesterol in human sera. Both the reactors and the peroxidase electrode retained over 90% of their original activities, even after repetitive use for 4 and 2 months, respectively.

3-Hydroxysteroid Dehydrogenases↗

PubMed1991

Total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol and coronary heart disease in Scotland.

OBJECTIVE: To investigate long term changes in total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol concentrations and in measures of other risk factors for coronary heart disease and to assess their importance for the development of coronary heart disease in Scottish men. DESIGN: Longitudinal study entailing follow up in 1988-9 of men investigated during a study in 1976. SETTING: Edinburgh, Scotland. SUBJECTS: 107 men from Edinburgh who had taken part in a comparative study of risk factors for heart disease with Swedish men in 1976 when aged 40. INTERVENTION: The men were invited to attend a follow up clinic in 1988-9 for measurement of cholesterol concentrations and other risk factor measurements. Eighty three attended and 24 refused to or could not attend. MAIN OUTCOME MEASURES: Changes in total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol concentrations, body weight, weight to height index, prevalence of smoking, and alcohol intake; number of coronary artery disease events. RESULTS: Mean serum total cholesterol concentration increased over the 12 years mainly due to an increase in the low density lipoprotein cholesterol fraction (from 3.53 (SD 0.09) to 4.56 (0.11) mmol/l) despite a reduction in high density lipoprotein cholesterol concentration. Body weight and weight to height index increased. Fewer men smoked more than 15 cigarettes/day in 1988-9 than in 1976. Blood pressure remained stable and fasting triglyceride concentrations did not change. The frequency of corneal arcus doubled. Alcohol consumption decreased significantly. Eleven men developed clinical coronary heart disease. High low density lipoprotein and low high density lipoprotein cholesterol concentrations in 1976, but not total cholesterol concentration, significantly predicted coronary heart disease (p = 0.05). Almost all of the men who developed coronary heart disease were smokers (91% v 53%, p less than 0.05). CONCLUSION: Over 12 years the lipid profile deteriorated significantly in this healthy cohort of young men. Smoking, a low high density lipoprotein concentration and a raised low density lipoprotein concentration were all associated with coronary heart disease in middle aged Scottish men, whereas there was no association for total cholesterol concentration. The findings have implications for screening programmes.

Adult↗

PubMed1988

Acyl coenzyme A:cholesterol acyl transferase in macrophages utilizes a cellular pool of cholesterol oxidase-accessible cholesterol as substrate.

Cholesterol esterification by acyl CoA:cholesterol acyl transferase (ACAT) in macrophages is a key process in atheroma foam cell formation. However, the process of cholesterol substrate delivery to ACAT is not well defined. In this study, J774 macrophages, which form foam cells with native low density lipoprotein (LDL), were labeled with [3H]cholesterol-containing liposomes. Most (80-90%) of the cholesterol label could be converted by cholesterol oxidase to cholestenone, suggesting plasma membrane localization; only 0.6% of the label was in cholesteryl ester (CE). In cells chased for 6 h in medium lacking LDL, the distribution of label was essentially unchanged, whereas in cells chased with LDL, 28% of the label was incorporated into CE concomitant with a decrease in cholestenone label to 50%. [3H]Cholesterol-labeled mouse peritoneal macrophages incubated with acetyl-LDL, and both J774 and mouse peritoneal macrophages incubated with 25-hydroxy-cholesterol, also showed a shift of label from cholestenone to CE. Similar results were found when cellular cholesterol was biosynthetically labeled with [3H]mevalonate. The percentage of cholesterol substrate for ACAT in LDL-treated J774 macrophages which originates from endogenous cellular pools (versus that originating from LDL itself) is approximately 50%. We conclude that upon activation of ACAT in macrophages, there is a novel process whereby a cholesterol oxidase-accessible pool of cellular cholesterol, presumably plasma membrane cholesterol, is translocated to ACAT in the endoplasmic reticulum.

3-Hydroxysteroid Dehydrogenases↗

PubMed1992

Dietary cholesterol fails to stimulate acylcoenzyme A: cholesterol acyltransferase activity in the liver of hamsters with a spontaneous high level of cholesterol.

The effect of exogenous cholesterol on acylcoenzyme A:cholesterol acyltransferase (ACAT) was investigated in conventional golden hamsters (NH) and in FEC hamsters characterized by a high level of cholesterol esters in the liver. ACAT activity was determined in liver microsomal fractions obtained from control animals, in animals fed 0.1% cholesterol diet or in microsomes preincubated with exogenous cholesterol. NH responded to cholesterol feeding by increasing the rate of cholesterol esterification in the liver, and exposure of the NH microsomes to media containing cholesterol stimulated ACAT activity. By comparison, whatever the conditions, cholesterol failed to alter the rate of cholesterol esterification in FEC hamsters. This finding raises several questions about cholesterol metabolism in the liver of these animals that does not fit into the well-established schemes of hepatic cholesterol metabolism.

Animals↗

PubMed1985

The absorption of cholesterol and the sterol balance in the Tarahumara Indians of Mexico fed cholesterol-free and high cholesterol diets.

The Tarahumara Indians of Mexico are habituated to a very low cholesterol, low fat diet and have lifelong low plasma cholesterol concentrations. To study cholesterol metabolism in these unusual people, 8 Tarahumara men were fed sequentially a cholesterol-free diet and then a diet containing 900 mg cholesterol under controlled conditions. The intestinal absorption of cholesterol, fecal steroid excretion and sterol balance were determined. During the high cholesterol diet period, the plasma cholesterol level increased from 113 +/- 8 mg/dl to 147 +/- 11 mg/dl (means +/- SD). Cholesterol biosynthesis decreased from 14.0 +/- 0.7 to 7.1 +/- 1.0 mg/kg/day (means +/- SE). The intestinal absorption of cholesterol was 27.7 +/- 6.7% (means +/- SE) during both dietary periods. Compared to other cultures, Tarahumaras had a reduced ability to absorb dietary cholesterol and higher total sterol turnover primarily because of an increased bile acid output. The total sterol disposition over three weeks of the high cholesterol diet accounted for all the absorbed dietary cholesterol.

Adult↗

PubMed1987

On the associations of body cholesterol pool size with age, HDL cholesterol and plasma total cholesterol concentration in humans.

Data from 17 subjects, in whom cholesterol kinetics had been measured by two-pool analysis of medium-term plasma cholesterol specific activity-time curves, were examined by multiple linear regression to explore the determinants of the size of the slowly exchanging cholesterol pool (MBmin) in humans. Pool size was independently and positively related to body weight (regression coefficient, 0.94 g per kg; P = 0.05) and age (1.77 g per year; P = 0.02). After allowance for these effects, MBmin retained a significant negative association with the plasma high density lipoprotein (HDL) cholesterol concentration (-0.56 g per mg/dl; P = 0.03), but was unrelated to plasma total cholesterol. This result is consistent with published data on the composition of those human tissues whose cholesterol is known to be largely a component of the slowly exchanging pool. It differs, however, from that of a recent study of cholesterol turnover [Blum et al, J. Lipid Res., 1985; 26: 1079-1088] in which pool size, measured by three-pool analysis of long-term decay curves, was unrelated to HDL and directly related to plasma total cholesterol. On the basis of other published data, it is considered that this discrepancy is unlikely to be a consequence of the difference between our respective studies in the duration and method of analysis of the specific activity decay curves. Differences in the variances of HDL cholesterol and plasma total cholesterol concentration that were examined, and in the biochemical-genetic factors underlying these variances, provide a more likely explanation. The overall weight of evidence favours the view that the pool of slowly exchangeable cholesterol in many human tissues expands during ageing at a rate which is increased in the presence of severe hypercholesterolemia, and which under some, but not all, circumstances also varies inversely with HDL cholesterol. The critical components of HDL metabolism which affect this process remain to be identified.

Adult↗

PubMed1990

Pancreatic cholesterol esterases. 3. Kinetic characterization of cholesterol ester resynthesis by the pancreatic cholesterol esterases.

The ability of cholesterol esterase to catalyze the synthesis of cholesterol esters has been considered to be of limited physiological significance because of its bile salt requirements for activity, though detailed kinetic studies have not been reported. This study was performed to determine the taurocholate, pH, and substrate requirements for optimal cholesterol ester synthesis catalyzed by various pancreatic lipolytic enzymes, including the bovine 67- and 72-kDa cholesterol esterases, human 100-kDa cholesterol esterase, and human 52-kDa triglyceride lipase. In contrast to current beliefs, cholesterol esterase exhibits a bile salt independent as well as a bile salt dependent synthetic pathway. For the bovine pancreatic 67- and 72-kDa cholesterol esterases, the bile salt independent pathway is optimal at pH 6.0-6.5 and is stimulated by micromolar concentrations of taurocholate. For the bile salt dependent synthetic reaction for the 67-kDa enzyme, increasing the taurocholate concentration from 0 to 1.0 mM results in a progressive shift in the pH optimum from pH 6.0-6.5 to pH 4.5 or lower. In contrast, cholesterol ester hydrolysis by the 67-, 72-, and 100-kDa enzymes was characterized by pH optima from 5.5 to 6.5 at all taurocholate concentrations. Optimum hydrolytic activity for these three enzyme forms occurred with 10 mM taurocholate. Since hydrolysis is minimal at low taurocholate concentrations, the rate of synthesis actually exceeds hydrolysis when the taurocholate concentration is less than 1.0 mM. The 52-kDa enzyme exhibits very low cholesterol ester synthetic and hydrolytic activities, and for this enzyme both activities are bile salt independent. Thus, our data show that cholesterol esterase has both bile salt independent and bile salt dependent cholesterol ester synthetic activities and that it may catalyze the net synthesis of cholesterol esters under physiological conditions.

Animals↗

PubMed1990

Regulation of cholesterol 7 alpha-hydroxylase in the liver. Purification of cholesterol 7 alpha-hydroxylase and the immunochemical evidence for the induction of cholesterol 7 alpha-hydroxylase by cholestyramine and circadian rhythm.

Two cholesterol 7 alpha-hydroxylase isozymes were purified from liver microsomes of cholestyramine-treated female rats by using anion exchange high performance liquid chromatography. These two cytochrome P-450 isozymes were similar in electrophoretic mobility, immunocross-reactivity, and Vmax but differed in Km for cholesterol, turnover number, and charges. Antibody against the major isozyme was raised in rabbit. This antibody specifically inhibited microsomal cholesterol 7 alpha-hydroxylase activity. Immunoblot of microsomal polypeptides indicated that microsomal cholesterol 7 alpha-hydroxylase enzyme levels were increased in parallel with cholesterol 7 alpha-hydroxylase activity upon the treatment of rats with diet supplemented with cholestyramine. Both cholesterol 7 alpha-hydroxylase activity and enzyme levels were drastically reduced immediately after the removal of cholestyramine from the diet. Cholesterol 7 alpha-hydroxylase activity was also detected in the microsomes of kidney, heart, and lung in about 7-27% of the level found in the liver. 3-Methylcholanthrene treatment induced cholesterol 7 alpha-hydroxylase activity and enzyme level. In contrast, pregnenolone-16 alpha-carbonitrile or dexamethasone treatment greatly depressed enzyme and activity in rats. Cholesterol 7 alpha-hydroxylase enzyme level was 2-3-fold higher in liver microsomes of rats maintained under the reversed light cycle than under the normal light cycle. In genetically obese Zucker rats, cholesterol 7 alpha-hydroxylase activity and enzyme level did not respond to the change in the light cycle, however, were induced to the same levels as in the lean rats by cholestyramine treatment. This study provided the first direct evidence that the bile acid feedback regulation and circadian rhythm of microsomal cholesterol 7 alpha-hydroxylase activity involved the induction of cholesterol 7 alpha-hydroxylase enzyme level.

Animals↗

PubMed1987

Cholesterol sulfate inhibits adrenal mitochondrial cholesterol side chain cleavage at a site distinct from cytochrome P-450scc. Evidence for an intramitochondrial cholesterol translocator.

Cholesterol sulfate inhibits (K1/2, 6 microM) the side chain cleavage of exogenous cholesterol in intact rat adrenal mitochondria. Inhibition is at a site other than cytochrome P-450scc: the spin state of the hemoprotein is not perturbed, and its activity is unaffected as judged by the failure to inhibit the metabolism both of 25-hydroxycholesterol and of endogenous cholesterol in a mitochondrial "steroidogenic pool." In contrast, 25-hydroxycholesterol, known to interact with the cytochrome, prevented the cleavage of both endogenous and exogenous cholesterol and produced the expected optical changes in the hemoprotein. Inhibition was specific, since a variety of related compounds including pregnenolone sulfate were not effective. Metabolic conversion to other species was insufficient to account for inhibition, indicating that cholesterol sulfate is the effective molecule. A hallmark of an inhibitor of a transport system is that disruption of the barrier to transport eliminates inhibition. Sonic disruption of mitochondria abated by 70% the effect of cholesterol sulfate, but did not affect inhibition by 25-hydroxycholesterol. Thus, the cholesterol sulfate appears to inhibit an intramitochondrial cholesterol translocation system that functions to move cholesterol into a steroidogenic pool. The high content of cholesterol sulfate in adrenal cortex (Drayer, N.M., Roberts, K.D., Bandi, L., and Lieberman, S. (1964) J. Biol. Chem. 239, 3112-3114) suggests a possible regulatory role for this molecule.

Adrenal Glands↗

PubMed1991

Cholesterol feeding increases plasma and aortic tissue cholesterol oxide levels in parallel: further evidence for the role of cholesterol oxidation in atherosclerosis.

To determine the relationship between plasma and arterial wall oxysterols, plasma and aortic tissue from 7 New Zealand White rabbits fed a high cholesterol (1%) diet for 6 weeks was compared to plasma and aortic tissue from 7 normocholesterolemic rabbits fed standard rabbit chow. Cholesterol and cholesterol oxide fractions were isolated and analyzed by gas chromatography. Normocholesterolemic plasma and aortic tissue contained low levels of cholest-5-ene-3 beta, 7 alpha-diol, cholesta-3,5-dien-7-one, 5,6 alpha-epoxy-5 alpha-cholestan-3 alpha-ol, cholest-5-ene-3 beta, 7 beta-diol, and 5 alpha-cholestane-3 beta, 5,6 beta-triol while hypercholesterolemic plasma and atherosclerotic aorta contained significantly higher levels (P less than 0.05) of these products. Furthermore, 5,6 beta-epoxy-5 alpha-cholestan-3 beta-ol not found in normocholesterolemic plasma or aortic tissue was present in substantial amounts in both hypercholesterolemic plasma and atherosclerotic aortic tissue. Cholest-5-ene-3 beta,25-diol and 3 beta-hydroxycholest-5-ene-7- one not present in normocholesterolemic aorta were present in the atherosclerotic aorta. The oxysterol chromatographic patterns of normocholesterolemic plasma and normocholesterolemic aortic tissue were similar to each other as were the oxysterol chromatographic patterns of hypercholesterolemic plasma and atherosclerotic aortic tissue. The chromatographic patterns between the normocholesterolemic and hypercholesterolemic samples differed however. Possible absorption of the low levels of cholesterol oxides present in the cholesterol feed could account for the elevation of only some of the oxysterols. We conclude that cholesterol oxides exist at some basal level in normocholesterolemia and that these levels are increased by cholesterol-feeding which results in hypercholesterolemia. Our findings demonstrate that there is a strong relationship between plasma and aortic arterial wall levels of cholesterol oxides and suggest that in addition to exogenous sources, formation of cholesterol oxides proceeds via free radical oxidation acting upon elevated cholesterol levels resulting in the accumulation of these potentially cytotoxic and atherogenic products.

Animals↗

PubMed1991

Pioglitazone hydrochloride inhibits cholesterol absorption and lowers plasma cholesterol concentrations in cholesterol-fed rats.

Diabetes is associated with altered cholesterol metabolism that may contribute to cardiovascular complications. Treatment of rats with pioglitazone hydrochloride, a novel antidiabetic compound that improves the general response of target cells to insulin, significantly lowered cholesterol levels in rats fed a hypercholesterolemic diet and produced a significant reduction in cholesterol absorption. Drug treatment was ineffective in rats that were not given dietary cholesterol. To determine whether these effects of pioglitazone hydrochloride might be related to the known ability of this compound to improve the response to circulating insulin, similar studies were conducted in streptozocin-induced diabetic rats with and without insulin replacement. Diabetic rats absorbed a greater percentage of dietary cholesterol than control rats. Treatment of insulin-deficient diabetic rats with pioglitazone alone did not affect cholesterol absorption; however, the combination of insulin and pioglitazone was synergistic to lower absorption of cholesterol and circulating cholesterol and triglycerides. Treatment of either normal rats or diabetic rats receiving insulin with pioglitazone hydrochloride produced a twofold decrease in the ratio of total cholesterol to high-density lipoprotein cholesterol. These results suggest that treatments that improve insulin sensitivity may also have a positive impact on coronary artery disease associated with diabetes.

Animals↗

PubMed1990

Day-to-day variability of serum cholesterol, triglyceride, and high-density lipoprotein cholesterol levels. Impact on the assessment of risk according to the National Cholesterol Education Program guidelines.

The National Cholesterol Education Program has recently published guidelines for the assessment of cardiovascular risk and goals for laboratory accuracy. To test the impact of biologic and analytic variability on the ability of a single lipid measurement to assess risk accurately, lipids were measured on three occasions in 51 volunteers. Notable day-to-day variability of total cholesterol (5%), triglyceride (20%), high-density lipoprotein cholesterol (10%), and calculated low-density lipoprotein cholesterol (8%) levels was found. Analytic variability contributed significantly to total variability of high-density lipoprotein cholesterol levels and calculated low-density lipoprotein cholesterol levels. Confidence intervals constructed around National Cholesterol Education Program cutoff points suggested that classification was reliable from a single measurement if total cholesterol value was below 4.78 (less than 185 mg/dL), between 5.56 and 5.81 (215 and 225 mg/dL), or above 6.59 mmol/L (greater than 225 mg/dL). Low-density lipoprotein cholesterol value classification from a single measurement was only accurate at below 3.00 (greater than 116 mg/dL) or above 4.50 mmol/L (greater than 174 mg/dL). This study documents significant day-to-day variability of serum lipids and suggests that patients near the National Cholesterol Education Program cutoff points may require repeated measurements to assign risk accurately.

Adult↗