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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↗
PubMed2006

Regulation of hepatic cholesterol metabolism in CETP/LDLr mice by cholesterol feeding and by drugs (cholestyramine and lovastatin) that lower plasma cholesterol.

1. The hepatic mechanisms involved in the simultaneous regulation of plasma cholesterol concentration and cholesteryl ester transfer protein (CETP) activity were investigated by sharply modifying the hepatic rates of cholesterol synthesis. This was accomplished by cholestyramine, lovastatin and cholesterol feeding in human CETP transgenic mice cross-bred with low-density lipoprotein receptor (LDLr)-knockout mice, generating CETP(+/-)/LDLr(+/-) mice, which present a plasma lipoprotein profile resembling that of humans. 2. Analyses of pooled data showed that the plasma CETP activity correlated positively with plasma total cholesterol concentration, hepatic CETP mRNA and the liver microsomal cholesterol content; a negative correlation was found between plasma CETP activity and the liver 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and LDLr mRNA levels. These coordinated events represent an efficient control system that stabilizes the cell cholesterol content. 3. Nonetheless, not all cholesterol metabolism regulatory systems seem to fit into a coherent pattern of responses, suggesting that other unknown cellular mechanisms play roles depending on the type of pharmacological intervention. 4. For example, microsomal cholesterol content was not affected by cholestyramine, but was increased on cholesterol feeding (as predicted), and, surprisingly, on lovastatin treatment. Furthermore, although both plasma cholesterol-lowering drugs increased CYP7A1 mRNA and had no effect on CYP27 mRNA, other metabolic components were differentially modified. Cholestyramine and lovastatin, respectively, did not modify and increased both HMG-CoA and sterol responsive element binding protein 1c mRNA, did not modify and lowered liver X receptor alpha mRNA, lowered and increased ATP binding cassette A1 mRNA and lowered and did not modify scavenger receptor B1 mRNA. 5. That is, different to unabsorbed cholestyramine, lovastatin, as an absorbed plasma cholesterol-lowering drug, may have modified the activity of other unknown genes that play roles in the interaction of CETP with the metabolism of hepatic cholesterol.

Animals↗
PubMed1995

Translocation of both lysosomal LDL-derived cholesterol and plasma membrane cholesterol to the endoplasmic reticulum for esterification may require common cellular factors involved in cholesterol egress from the acidic compartments (lysosomes/endosomes).

Using a stable cell line 25-RA derived from wild-type Chinese hamster ovary (CHO) cells as the parental cell, this laboratory previously reported the isolation and characterization of CHO cell mutants (cholesterol-trafficking or CT) defective in transporting LDL-derived cholesterol out of the acidic compartment(s) (lysosomes/endosomes) to the endoplasmic reticulum (ER) for esterification. In this report, we show that the CT mutation can be complemented by fusion with human cells; however, attempts to complement the CT defect through DNA transfection have resulted in a collection of stable cell lines designated as ST cells. Under cholesterol starvation condition, the ST cells exhibit an elevated rate of cholesterol ester biosynthesis (by 3- to 5-fold) compared to both the parental CHO cells and the CT cells. The phenotypes of the ST cells are stable. ST cells are thus new cell lines arisen from the CT cells. When the plasma membranes of the parental, CT, and ST cells are labelled with [3H]cholesterol, ST cells show rates of [3H]cholesterol esterification much higher than that observed in CT cells but lower than that observed in the parental CHO cells. This result shows that translocation of plasma membrane cholesterol to the ER for esterification is defective in the CT cells. This result also suggests that ST cells acquire increased cholesterol trafficking activity between the lysosome and the ER without mixing the plasma membrane cholesterol pool. The characteristics of CT cells and ST cells reported here suggest that translocation of both lysosomal LDL-derived cholesterol and plasma membrane cholesterol to the ER for esterification may require common cellular factors involved in cholesterol egress from the acidic compartment(s) (lysosomes/endosomes).

Animals↗
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↗
PubMed1994

Cholesterol distribution in renal epithelial cells LLC-PK1 as determined by cholesterol oxidase: evidence that glutaraldehyde fixation masks plasma membrane cholesterol pools.

Treatment with cholesterol oxidases has shown that cholesterol is heterogeneously distributed in brush border membranes isolated from the apical domain of the renal and intestinal epithelial cells [Bloj, B., & Zilversmit, D. B. (1982) J. Biol. Chem. 257, 7608-7614; El Yandouzi, E. H., & Le Grimellec, C. (1992) Biochemistry 31, 547-551]. Cholesterol distribution between plasma membrane and intracellular membranes of the corresponding cells remains unexplored. The effects of Brevibacterium sp. cholesterol oxidase on the cholesterol content of LLC-PK1 cells, an epithelial cell line with multiple differentiated characteristics of the renal proximal tubule, were investigated. In confluent living cells grown as a monolayer on solid support, a small but significant fraction (13%) of the cholesterol was oxidized during the first hour of the oxidase treatment. Glutaraldehyde fixation prior to treatment resulted in a nearly complete (86.1 +/- 1.8) oxidation of the cellular cholesterol according to first-order kinetics. Filipin labeling and oxidation at 15 degrees C confirmed that cholesterol was essentially confined to the plasma membrane in LLC-PK1 cells. When adding the oxidase either on the apical or on the basolateral side of cells grown on permeant support and fixed with glutaraldehyde, a comparable monophasic oxidation of cholesterol was observed, despite the presence of efficient tight junctions. Adding the oxidase to both sides simultaneously did not increase the rate of oxidation. Finally, fixation of isolated renal brush border membranes with glutaraldehyde rendered undiscernible their cholesterol pools. We conclude that glutaraldehyde fixation, a commonly used process in the analysis of cholesterol distribution in cells, can mask the existence of cholesterol pools in plasma membranes.

Brevibacterium↗
PubMed2002

Cholesterol treatment forever? The first Scandinavian trial of cholesterol supplementation in the cholesterol-synthesis defect Smith-Lemli-Opitz syndrome.

OBJECTIVES: To investigate if exogenous cholesterol affects sterol turnover in the cholesterol-synthesis defect Smith-Lemli-Opitz syndrome (SLOS) and if clinical effects justify long-time supplementation. The SLOS is caused by a deficiency of the enzyme 7-dehydrocholesterol-7-reductase with markedly reduced cholesterol levels and greatly increased levels of 7-dehydrocholesterol (7-DHC). DESIGN: Treatment with dietary cholesterol in patients with SLOS in a case series study. SETTING: All biochemical analyses were performed in one laboratory. The clinical follow-up was carried out by one of the authors (LS), a paediatric neurologist. SUBJECTS: Seven patients with biochemically verified SLOS have been diagnosed in Sweden and all of them are included in the study. INTERVENTIONS: Six patients were treated for 0.5-6 years orally with cholesterol and the bile acid taurocholate and one patient was supplemented with cholesterol only. MAIN OUTCOME MEASURES: In addition to cholesterol, 7- and 8-DHC, lathosterol was used as a marker of endogenous cholesterol synthesis and the patients were followed clinically. Nerve conduction velocities (NCV) were measured before treatment in all patients and a UVA-light test was performed in one of them. RESULTS: Lathosterol was initially increased by cholesterol supply in subjects with very low cholesterol levels with subsequent rise of 7- and 8-DHC. Photosensitivity clinically improved in all, verified by UVA-light testing in one. Progressive polyneuropathy improved, whilst stationary forms did not. CONCLUSION: Dietary cholesterol can up-regulate sterol turnover in severely affected patients. Although some specific features are treatable and verifiable by objective methods, data supporting life-long treatment dietary cholesterol in all SLO patients are still lacking.

Age Factors↗
PubMed1996

Hepatic cholesterol metabolism in patients with cholesterol gallstones: enhanced intracellular transport of cholesterol.

BACKGROUND & AIMS: Alterations of hepatic cholesterol metabolism in patients with cholesterol gallstones are still controversial. This study investigated whether hepatic cholesterol metabolism is altered in Japanese patients with cholesterol gallstones. METHODS: In this systematic study of 24 middle-aged nonobese and nondiabetic Japanese patients who had cholesterol gallstones and were undergoing elective cholecystectomy, an analysis of three regulatory enzymes in the cholesterol metabolism, as well as cytosolic total and free cholesterol levels and sterol carrier protein 2/nonspecific lipid transfer protein (SCP2/nsLTP) levels, was conducted using liver biopsy samples obtained during surgery. RESULTS: The activities of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase, and acyl-CoA/cholesterol acyltransferase were not significantly different between patients and controls. Nevertheless, patients with gallstones showed tendencies for elevated HMG-CoA reductase activity and protein content and decreased cholesterol 7 alpha-hydroxylase activities. As anticipated, serum levels of 7 alpha-hydroxycholesterol and squalene paralleled these findings. The patients with gallstones also had significantly increased cytosolic total and free cholesterol levels (P < 0.001), which correlated strongly with increased cytosolic levels of SCP2/nsLTP (r = 0.80, P < 0.001 and r = 0.81, P < 0.001, respectively). CONCLUSIONS: The results suggest that intracellular cholesterol transport is enhanced in patients with cholesterol gallstones.

Adult↗
PubMed1996

Exogenous hypercholesterolemic rats, compared with their progenitor, Sprague-Dawley rats, promptly alter cholesterol metabolism in the liver and secrete cholesterol-rich particles in response to dietary cholesterol.

Early responses of cholesterol metabolism to dietary cholesterol were compared between exogenous hypercholesterolemic (ExHC) and Sprague-Dawley rats. Both strains had a similar radioactivity of [14C]cholesterol in the serum half a day after the oral administration, but thereafter the radioactivity disappeared slowly in ExHC rats. ExHC rats promptly altered in response to the dietary cholesterol, activities of cholesterol 7 alpha-hydroxylase and cholesterol synthesis in the liver and fecal excretion of bile acids derived from [14C]cholesterol administered orally. Lymphatic transport for 24 hr [14C]cholesterol was similar between the strains. Triton administration resulted in a marked accumulation of cholesterol in serum d > 1.006 g/mL lipoproteins in ExHC rats; in addition, the formation of cholesteryl esters from [14C]oleic acid intravenously infused was greater in ExHC rats. These results indicate that ExHC rats increase serum cholesterol in response to exogenous cholesterol by decreasing the liver uptake and enhancing the secretion in the liver.

Animals↗
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↗
PubMed1993

Plasma total and lipoprotein cholesterol, liver cholesterol and fecal cholesterol excretion in hamsters fed fiber diets.

The effect of dietary fibers on plasma lipids, liver cholesterol and fecal cholesterol excretion was investigated in hamsters. Male 9- to 11-wk-old Golden-Syrian hamsters (n = 155) were fed a purified hypercholesterolemic diet (0.1% cholesterol, 10% fat) for 5 wk to elevate plasma lipid concentrations. Sixteen animals with elevated plasma total cholesterol were randomly assigned to each treatment group: control, oat bran, guar gum, cellulose, xylan and terminal groups. After 4 wk of fiber diet consumption, the plasma total cholesterol concentrations were significantly decreased in the oat bran, guar gum and xylan groups (16, 12 and 15%, respectively) (P < 0.05). Plasma HDL cholesterol concentration was significantly decreased only in the guar gum group (12%) (P < 0.05). The combined plasma VLDL+LDL cholesterol concentrations were significantly lowered by the oat bran, xylan and cellulose diets (38, 34 and 40%, respectively) (P < 0.05). After 4 wk of control diet consumption, the liver cholesterol concentration quadrupled to 10.6 mumol cholesterol/g liver (P < 0.05). After 4 wk of consumption of the treatment diets, liver cholesterol was further increased (P < 0.05) only in the cellulose group, to 14.5 mumol cholesterol/g liver. The total fecal cholesterol excretion was the highest (P < 0.05) in the oat bran group. In the present study, oat bran, guar gum and xylan were effective hypocholesterolemic agents in hamsters.

Animals↗
PubMed1998

Dietary taurine supplementation reduces plasma and liver cholesterol and triglyceride levels in rats fed a high-cholesterol or a cholesterol-free diet.

The effects of dietary taurine supplementation on plasma and hepatic lipid levels and phospholipid profiles were evaluated in rats fed a high-cholesterol or a cholesterol-free diet. Four groups of male rats were fed one of the following diets for 5 weeks: cholesterol-free diet (CFD); high cholesterol diet (HCD); high cholesterol, high taurine diet (HCHTD); or high taurine diet (HTD). Rats fed a HCHTD had significantly lower plasma levels of total cholesterol (32% reduction), LDL-cholesterol (37% reduction) and triglyceride (43% reduction) than rats fed a HCD alone. Plasma concentrations of total cholesterol, LDL-cholesterol and triglyceride were also significantly reduced in rats fed a HTD compared to rats fed a CFD. Taurine supplementation to the HCD significantly reduced hepatic cholesterol (50% decrease) and triglyceride (30% decrease) levels in rats. Taurine supplementation to the CFD also significantly reduced the hepatic triglyceride concentration (43% decrease) and elevated hepatic free fatty acid levels (77% increase) compared to rats fed only a CFD. These results suggest that dietary taurine supplementation is both hypocholesterolemic and hypotriglyceridemic in rats whose body cholesterol status is high or normal.

Animals↗
PubMed1999

Lack of effect of cholesterol esterase inhibitor CVT-1 on cholesterol absorption and LDL cholesterol in humans.

Two clinical trials were performed to test the hypothesis that CVT-1, a potent inhibitor of pancreatic cholesterol esterase, reduces percent cholesterol absorption and LDL cholesterol in humans. Measurements of cholesterol absorption were made with deuterated cholesterol tracers given orally and intravenously and detected in plasma by a new technique using negative ion mass spectrometry. Study 1 was a randomized, double-blind parallel study of CVT-1 treatment at doses of 0, 300, 1500, and 3000 mg/day in 19 subjects. Percent cholesterol absorption measured at baseline and again after 2 and 6 weeks showed no treatment effect and LDL cholesterol was unchanged. Study II was a randomized open-label crossover comparison between CVT-1 given as 1000 mg three times daily for 2 weeks and 187.5 mg hourly 16 hours/day for 2 weeks. Percent cholesterol absorption and plasma LDL cholesterol were not different between periods. We conclude that cholesterol esterase is not required for unesterified cholesterol absorption in human subjects.

Cellulose↗
PubMed2002

Effect of SMP-500, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on serum cholesterol level and LDL cholesterol clearance in hamsters with induced hyperlipidemia.

The effect of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on serum cholesterol levels was investigated in hyperlipidemic hamsters whose condition had been preestablished by diet. SMP-500 reduced the total serum cholesterol level in a dose-dependent manner. SMP-500 also reduced the hepatic free cholesterol content and markedly reduced the esterified cholesterol content compared with the control group. Interestingly, SMP-500 at a dose of 30 mg/kg increased LDL clearance in vivo. As SMP-500 at this dose potently lowered the total serum cholesterol level, the increased LDL clearance was identified as another mechanism for the cholesterol-lowering effect of SMP-500. However, unlike HMG CoA reductase inhibitors, SMP-500 did not affect cholesterol biosynthesis in HepG2 cells. Therefore the etiology of the increased LDL clearance is not yet clear, but the reduced hepatic free cholesterol may play an important role in this process. These results suggest that the cholesterol-lowering effect of SMP-500 is due, not only to the inhibition of ACAT, but also to the increase in cholesterol clearance from the blood. This finding supports the therapeutic potential of SMP-500 for the treatment of human hypercholesterolemia.

Animals↗
PubMed2006

Different cellular traffic of LDL-cholesterol and acetylated LDL-cholesterol leads to distinct reverse cholesterol transport pathways.

Endocytosis of LDL and modified LDL represents regulated and unregulated cholesterol delivery to macrophages. To elucidate the mechanisms of cellular cholesterol transport and egress under both conditions, various primary macrophages were labeled and loaded with cholesterol or cholesteryl ester from LDL or acetylated low density lipoprotein (AcLDL), and the cellular cholesterol traffic pathways were examined. Confocal microscopy using fluorescently labeled 3,3'-dioctyldecyloxacarbocyanine perchlorate-labeled LDL and 1,1'-dioctyldecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate-labeled AcLDL demonstrated their discrete traffic pathways and accumulation in distinct endosomes. ABCA1-mediated cholesterol efflux to apolipoprotein A-I (apoA-I) was much greater for AcLDL-loaded macrophages compared with LDL. Treatment with the liver X receptor ligand 22-OH increased efflux to apoA-I in AcLDL-loaded but not LDL-loaded cells. In contrast, at a level equivalent to AcLDL, LDL-derived cholesterol was preferentially effluxed to HDL, in keeping with increased ABCG1. In vivo studies of reverse cholesterol transport (RCT) from cholesterol-labeled macrophages injected intraperitoneally demonstrated that LDL-derived cholesterol was more efficiently transported to the liver and secreted into bile than AcLDL-derived cholesterol. This indicates a greater efficiency of HDL than lipid-poor apoA-I in interstitial fluid in controlling in vivo RCT. These assays, taken together, emphasize the importance of mediators of diffusional cholesterol efflux in RCT.

ATP Binding Cassette Transporter 1↗
PubMed2005

Assessment of modes of action and efficacy of plasma cholesterol-lowering drugs: measurement of cholesterol absorption, cholesterol synthesis and bile acid synthesis and turnover using novel stable isotope techniques.

Several processes are involved in control of plasma cholesterol levels, e.g., intestinal cholesterol absorption, endogenous cholesterol synthesis and transport and bile acid synthesis. Adaptation of either of these processes allows the body to adapt to changes in dietary cholesterol intake. Disturbances herein may lead to hypercholesterolemia and increase the risk for atherosclerosis. Several approaches are available for plasma-cholesterol lowering therapies, particularly aimed at reduction of low-density lipoprotein (LDL) cholesterol. Currently used therapies aim to decrease (hepatic) cholesterol synthesis, to inhibit cholesterol absorption or to stimulate bile acid synthesis. The latter can be achieved by reducing bile acid absorption to alleviate the negative feedback control exerted by bile acids circulating in the body. Approaches to directly stimulate bile acid synthesis may become available. Novel drugs should be tested on the efficiency to influence their actual targets. Several techniques are available to measure cholesterol absorption, cholesterol synthesis and bile acid synthesis and absorption in vivo in human subjects. The most reliable techniques are based on the use of stable isotopes and mass spectrometry. This paper provides a condensed background on physiological parameters that determine cholesterol homeostasis, and potential new mechanisms of drug action and focuses, especially, on new techniques to monitor the effects of drugs in humans.

Animals↗
PubMed1993

Effect of dietary fat and cholesterol level on tissue cholesterol concentrations of growing pigs selected for high or low serum cholesterol.

Thirty-six female pigs selected for three generations for high or low serum cholesterol were chosen to evaluate the effects of a high-fat, high-cholesterol diet and a low-fat, low-cholesterol diet provided on an ad libitum basis for 92 d beginning at 12 wk of age on the cholesterol content and percentage of fat in muscle and organ tissues. The pigs were four-way crosses (Chester White x Landrace x Large White x Yorkshire). Samples of cerebrum, heart, ileum, kidney, liver, longissimus muscle, semitendinosus muscle, and subcutaneous fat were collected from each animal for determination of cholesterol concentration. The liver was the only tissue that had a significant difference in cholesterol content and in fat percentage between the genetic groups (high serum cholesterol and low serum cholesterol) and between the two diets (high-fat, high-cholesterol diet and low-fat, low-cholesterol diet). There were no interactions between diet and genetic background on cholesterol accretion or on the percentage of fat in the tissues.

Adipose Tissue↗