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S D Turley

Publications and source records attributed to S D Turley.

At least 19 recordsLinked to original sources
PubMed1999

Cholesterol accumulation in tissues of the Niemann-pick type C mouse is determined by the rate of lipoprotein-cholesterol uptake through the coated-pit pathway in each organ.

Niemann-Pick type C (NPC) disease is associated with the accumulation of unesterified cholesterol in nearly all tissues and with progressive neurodegeneration. A murine model of this disease, the NPC mouse, was used to determine whether this sequestered cholesterol represented sterol carried in low density lipoprotein (LDL) and chylomicrons (CMs) taken up into the tissues through the coated-pit pathway. By 7 weeks of age, the sterol pool in the NPC mice had increased from 2,165 to 5,669 mg/kg body weight because of the daily sequestration of 67 mg of cholesterol per kg in the various organs. This was 7-fold greater than the rate of accumulation in control mice. The rate of LDL clearance in the NPC mouse was normal (523 ml/day per kg) and accounted for the uptake of 78 mg/day per kg of cholesterol in LDL whereas 8 mg/day per kg was taken up from CMs. Deletion of the LDL receptor in NPC mice altered the concentration of unesterified cholesterol in every organ in a manner consistent with the changes also observed in the rate of LDL cholesterol uptake in those tissues. Similarly, altering the flow of cholesterol to the liver through the CM pathway changed the concentration of unesterified cholesterol in that organ. Together, these observations strongly support the conclusion that, in NPC disease, it is cholesterol carried in LDL and CMs that is sequestered in the tissues and not sterol that is newly synthesized and carried in high density lipoprotein.

Adrenal Glands↗
PubMed1999

Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein.

Type C Niemann-Pick disease is due to a mutation in Niemann-Pick C (NPC) protein, a putative determinant of intracellular cholesterol transport. This study quantifies cholesterol balance in vivo across all tissues in mice with this defect. Cholesterol balance in the heterozygous animal is normal, but in the homozygous mouse the whole animal cholesterol pool expands continuously from birth, reaching 5, 442 mg/kg at 7 wk. The size of this pool in each organ is proportional to the rate at which each tissue clears low-density lipoprotein-cholesterol. Despite this expansion, however, cholesterol synthesis is increased so that whole animal synthesis equals 180 mg. day-1. kg-1. Forcing additional cholesterol into the liver through the clathrin-coated pit pathway increases the hepatic cholesterol pool in control mice, all of which is esterified, while there is a much greater increase in this pool in mutant mice, all of which is unesterified. These findings are consistent with the view that there is a block in sterol movement from the lysosome to the sites of regulation in NPC disease and have important implications for understanding the function of the NPC protein in intracellular cholesterol metabolism, in general, and in the brain, in particular.

Animals↗
PubMed1999

Genetic differences in cholesterol absorption in 129/Sv and C57BL/6 mice: effect on cholesterol responsiveness.

This study compared the cholesterolemic response of two strains of mice with genetically determined differences in cholesterol absorption. When fed a basal low-cholesterol diet, 129/Sv mice absorbed cholesterol twice as efficiently as did C57BL/6 mice (44% vs. 20%). Total lipid absorption, in contrast, averaged 80-82% in both strains. The higher level of cholesterol absorption in the 129/Sv animals was reflected in an adaptive reduction in hepatic and intestinal sterol synthesis. When fed lipid-enriched diets, the 129/Sv mice became significantly more hypercholesterolemic and had twofold higher hepatic cholesterol concentrations than did the C57BL/6 animals even though the conversion of cholesterol to bile acids was stimulated equally in both strains. The difference in cholesterol absorption between these mouse strains was not the result of physicochemical factors relating to the size and composition of the intestinal bile acid pool but more likely reflects an inherited difference in one or more of the biochemical steps that facilitate the translocation of sterol across the epithelial cell.

Animals↗
PubMed1998

Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha.

We demonstrate that mice lacking the oxysterol receptor, LXR alpha, lose their ability to respond normally to dietary cholesterol and are unable to tolerate any amount of cholesterol in excess of that which they synthesize de novo. When fed diets containing cholesterol, LXR alpha (-/-) mice fail to induce transcription of the gene encoding cholesterol 7alpha-hydroxylase (Cyp7a), the rate-limiting enzyme in bile acid synthesis. This defect is associated with a rapid accumulation of large amounts of cholesterol in the liver that eventually leads to impaired hepatic function. The regulation of several other crucial lipid metabolizing genes is also altered in LXR alpha (-/-) mice. These results demonstrate the existence of a physiologically significant feed-forward regulatory pathway for sterol metabolism and establish the role of LXR alpha as the major sensor of dietary cholesterol.

Alkyl and Aryl Transferases↗
PubMed1998

Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets.

These studies were undertaken to determine whether in young adult outbred CD-1 mice there were any gender-related differences in basal bile acid metabolism that might be important in determining how males and females in this species responded to a dietary cholesterol challenge. When fed a plain cereal-based rodent diet without added cholesterol, 3-month-old females, compared with age-matched males, manifested a significantly larger bile acid pool (89.1 vs. 54.1 micromol/100 g body weight), a higher rate of fecal bile acid excretion (13.6 vs. 8.5 micromol/d/100 g body weight), a more efficient level of intestinal cholesterol absorption (41.1% vs. 25. 3%), and a lower rate of hepatic sterol synthesis (338 vs. 847 nmol/h/g). Similar results were found in C57BL/6 and 129Sv inbred mice. In matching groups of CD-1 mice fed a diet containing 1% cholesterol for 21 days, hepatic cholesterol levels increased much more in the females (from 2.4 to 9.1 mg/g) than in the males (from 2. 1 to 5.2 mg/g). This occurred even though the level of stimulation of cholesterol 7-hydroxylase activity in the females (79%) exceeded that in the males (55%), as did the magnitude of the increase in fecal bile acid excretion (females: 262% vs. males: 218%). However, in both sexes, bile acid pool size expanded only modestly and by a comparable degree (females: 19% vs. males: 26%) so that in the cholesterol-fed groups, the pool remained substantially larger in the females than in the males (102.3 vs. 67.6 micromol/100 g body weight). Together, these data demonstrate that while male and female CD-1 mice do not differ qualitatively in the way cholesterol feeding changes their bile acid metabolism, the inherently larger bile acid pool in the female likely facilitates the delivery of significantly more dietary cholesterol to the liver than is the case in males, thereby resulting in higher steady-state hepatic cholesterol levels.

Animal Feed↗
PubMed1998

Preferential utilization of newly synthesized cholesterol for brain growth in neonatal lambs.

These studies used the suckling lamb as a model to determine the sources of cholesterol that are utilized for development of the central nervous system in the neonate. Lambs were studied at 1.3 and 16.4 days after birth. Over this 15-day interval, 14 g of new brain tissue were formed. About 9-10 mg of cholesterol were utilized daily for this new tissue growth. To determine the source of this cholesterol, the absolute rates of low-density lipoprotein clearance and cholesterol synthesis were measured in vivo in nine separate regions of the central nervous system. Low-density lipoprotein clearance throughout the brain was very low and at most could have contributed only 0.3-0.4 mg cholesterol daily for new brain growth. In contrast, the brain synthesized 7-8 mg of cholesterol/day. There were pronounced regional differences in the concentration of cholesterol throughout the brain, and these correlated closely with the rate of sterol synthesis (r = 0.95) in these same regions. We conclude that the principal source of sterol for brain growth in suckling lambs is de novo synthesis.

Aging↗
PubMed1998

Phase III interlaboratory study of FETAX, Part 2: interlaboratory validation of an exogenous metabolic activation system for frog embryo teratogenesis assay--Xenopus (FETAX).

Interlaboratory validation of an exogenous metabolic activation system (MAS) developed for the alternative, short-term developmental toxicity bioassay, Frog Embryo Teratogenesis Assay-Xenopus (FETAX) was performed with cyclophosphamide and caffeine. Seven study groups within six separate laboratories participated in the study in which three definitive concentration-response experiments were performed with and without the MAS in a side-by-side format for each chemical. Since both chemicals had been previously tested in FETAX, the test concentrations were provided to each laboratory prior to testing. Interlaboratory coefficient of variation (CV) values for unactivated cyclophosphamide (no MAS) were 15%, 15%, 29%, and 25% for the 96-hr LC50, 96-hr EC50 (malformation), Minimum Concentration to Inhibit Growth (MCIG), and Teratogenic Index (TI) values, respectively. Addition of the MAS increased the CV values of each endpoint at least 3.9-fold. Interlaboratory CV values for unactivated caffeine were 31%, 18%, 31%, and 46% for the 96-hr LC50, 96-hr EC50 (malformation), MCIG, and TI values, respectively. Addition of the MAS decreased the CV values of each respective endpoint by at least 1.6-fold. Results indicated that bioactivated toxicants may be prone to greater variability in response amongst laboratories than compounds, which are detoxified. Even though more variability was noted with activated cyclophosphamide, results were within interlaboratory variation expected for other aquatic-based bioassays. Thus, results from these studies warrant the continued use and further refinement of FETAX for alternative developmental toxicity assessment.

Abnormalities, Drug-Induced↗
PubMed1998

Marked reduction in bile acid synthesis in cholesterol 7alpha-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia.

These studies used mice that were deficient in cholesterol 7alpha-hydroxylase to determine the effects of reduced bile acid synthesis on cholesterol homeostasis. In mice lacking this enzyme, bile acid synthesis was reduced from 8.3 to 3.4 micromol/day per 100 g body weight, the intestinal bile acid pool was decreased from 62.5 to 13.2 micromol/100 g bw, and the proportion of hyodeoxycholate, relative to cholate, in this pool was significantly increased. Associated with these changes, intestinal cholesterol absorption decreased from 37% to <1% while triacylglycerol absorption and animal weight gain remained essentially unaffected. The very low rate of cholesterol absorption could be corrected by feeding the mutant mice cholate, but not hyodeoxycholate. The reduction in sterol uptake across the intestine was associated with a 2-fold increase in cholesterol synthesis in the small bowel and liver and an increase in fecal neutral sterol excretion from 15.2 to 35.7 micromol/day per 100 g bw. The size of the cholesterol pools in the plasma, various organs and whole animal remained constant. Thus, under circumstances where the excretion of sterol as bile acids was markedly reduced, total cholesterol turnover actually increased from 164 to 239 mg/day per kg bw. This study demonstrates the complex interactions between bile acid and cholesterol metabolism and the dramatic effects of eliminating a single gene product; however, even though a major catabolic pathway was deleted, cholesterol balance across the animal was maintained.

Animals↗
PubMed1998

Centripetal cholesterol flux to the liver is dictated by events in the peripheral organs and not by the plasma high density lipoprotein or apolipoprotein A-I concentration.

The major net flux of cholesterol in the intact animal or human is from the peripheral organs to the liver. This flux is made up of cholesterol that is either synthesized in these peripheral tissues or taken up as lipoprotein cholesterol. This study investigates whether it is the concentration of apolipoprotein (apo) A-I or high density lipoprotein in the plasma that determines the magnitude of this flux or, alternatively, whether events within the peripheral cells themselves regulate this important process. In mice that lack apoA-I and have very low concentrations of circulating high density lipoprotein, it was found that there was no accumulation of cholesterol in any peripheral organ so that the mean sterol concentration in these tissues was the same (2208 +/- 29 mg/kg body weight) as in control mice (2176 +/- 50 mg/kg). Furthermore, by measuring the rates of net cholesterol acquisition in the peripheral organs from de novo synthesis and uptake of low density lipoprotein, it was demonstrated that the magnitude of centripetal sterol movement from the peripheral organs to the liver was virtually identical in control animals (78 +/- 5 mg/day per kg) and in those lacking apoA-I (72 +/- 4 mg/day per kg). These studies indicate that the magnitude of net sterol flux through the body is not related to the concentration of high density lipoprotein or apolipoprotein A-I in the plasma, but is probably determined by intracellular processes in the peripheral organs that dictate the rate of movement of cholesterol from the endoplasmic reticulum to the plasma membrane.

Animals↗
PubMed1997

The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation.

Lowering of the elevated plasma FFA concentration in 18- 24-h fasted rats with nicotinic acid (NA) caused complete ablation of subsequent glucose-stimulated insulin secretion (GSIS). Although the effect of NA was reversed when the fasting level of total FFA was maintained by coinfusion of soybean oil or lard oil (plus heparin), the more saturated animal fat proved to be far more potent in enhancing GSIS. We therefore examined the influence of individual fatty acids on insulin secretion in the perfused rat pancreas. When present in the perfusion fluid at 0.5 mM (in the context of 1% albumin), the fold stimulation of insulin release from the fasted pancreas in response to 12.5 mM glucose was as follows: octanoate (C8:0), 3.4; linoleate (C18:2 cis/cis), 5.3; oleate (C18:1 cis), 9.4; palmitate (C16:0), 16. 2; and stearate (C18:0), 21.0. The equivalent value for palmitoleate (C16:1 cis) was 3.1. A cis--> trans switch of the double bond in the C16:1 and C18:1 fatty acids had only a modest, if any, impact on their potency. A similar profile emerged with regard to basal insulin secretion (3 mM glucose). When a subset of these fatty acids was tested in pancreases from fed animals, the same rank order of effectiveness at both basal and stimulatory levels of glucose was seen. The findings reaffirm the essentiality of an elevated plasma FFA concentration for GSIS in the fasted rat. They also show, however, that the insulinotropic effect of individual fatty acids spans a remarkably broad range, increasing and decreasing dramatically with chain length and degree of unsaturation, respectively. Thus, for any given level of glucose, insulin secretion will be influenced greatly not only by the combined concentration of all circulating (unbound) FFA, but also by the makeup of this FFA pool. Both factors will likely be important considerations in understanding the complex interplay between the nature of dietary fat and whole body insulin, glucose, and lipid dynamics.

Animals↗
PubMed1997

Regulation of fecal bile acid excretion in male golden Syrian hamsters fed a cereal-based diet with and without added cholesterol.

The objective of these studies was to investigate the comparative physiology and regulation of bile acid metabolism in the male Golden Syrian hamster by measuring the rate of fecal bile acid excretion and bile acid pool size in animals fed a cereal-based diet either alone, or with added cholesterol or cholestyramine. In group-housed hamsters fed only the plain diet fecal bile acid excretion in animals at 6, 10, and 15 weeks of age averaged 11.0, 8.0, and 6.9 mumol/d per 100 g body weight (bw), respectively. Pool size, measured by subtracting from the total amount of bile acid washed out over 12 hours of biliary diversion the amount of bile acid excreted in the stools over the same period, equalled 17.8 mumol/100 g bw in 15-week-old hamsters fed the plain diet. Hence, under basal conditions, these animals turned over about 38% of their bile acid pool daily. In hamsters fed a diet with 3% cholestyramine for 18 days, fecal bile acid excretion averaged 20.6 mumol/d per 100 g bw, and the pool size contracted to 5.8 mumol/100 g bw. In matching animals fed a diet containing 0.12% cholesterol for 30 days, hepatic cholesterol levels increased from 1.9 +/- 0.1 to 12.6 +/- 0.7 mg/g, fecal bile acid excretion increased marginally from 5.8 to 8.0 mumol/day per 100 g bw, while pool size was unchanged (16.6 mumol/100 g bw). When the cholesterol content of the diet was raised to 1.0%, hepatic cholesterol levels reached 66.5 +/- 2.6 mg/g, but bile acid excretion remained at 8 mumol/d per 100 g bw. These data define some of the basal features of bile acid metabolism in the hamster, and substantiate the view that the marked cholesterolemic response of this species may relate partly to a limited ability to convert dietary cholesterol to bile acid.

Animals↗
PubMed1997

Identification of a metabolic difference accounting for the hyper- and hyporesponder phenotypes of cynomolgus monkey.

These studies were done to determine whether an underlying metabolic difference could account for the higher concentration of cholesterol carried in low density lipoproteins (LDL-C) in male hyperresponder (HR) cynomolgus monkeys than in their hyporesponder (HO) counterparts during dietary cholesterol challenge. All animals were fed to steady state at 5 months a diet that had a constant concentration of cholesterol (0.19 mg/g), triacylglycerol (175 mg/g), and soluble fiber. There were no differences in these two phenotypes with respect to the profile of fatty acids in the liver and bile acids in the gallbladder, or in the relationship of cholesterol synthesis to cholesteryl ester formation in the liver. The rate of cholesterol synthesis in all extrahepatic tissues was also the same in the HO and HR animals but was 2.1 mg/day per kg body weight less in the liver of the HR monkeys. When challenged with a greater dietary cholesterol load, therefore, the HR animal could not readily further down-regulate synthesis and so shifted more cholesterol into the ester pool (9.4 mg/g) than did the HO animal (3.9 mg/g). Also the LDL-C concentration was more markedly elevated (412 mg/dl) compared to the hyporesponder monkey (188 mg/dl). Thus, this single metabolic alteration apparently accounted for the HO and HR phenotypes. As this difference was not due to variation in the delivery of sterol from the extrahepatic organs to the liver, it must reflect a difference in either net intestinal sterol absorption or net hepatic sterol excretion in the two phenotypes.

Animals↗
PubMed1996

Effect of feeding psyllium and cholestyramine in combination on low density lipoprotein metabolism and fecal bile acid excretion in hamsters with dietary-induced hypercholesterolemia.

We wished to determine the effectiveness of submaximal doses of cholestyramine and psyllium given in combination in reversing dietary-induced hypercholesterolemia in Golden Syrian hamsters, and to investigate the mechanism or mechanisms of action through which these agents together decrease plasma low density lipoprotein cholesterol (LDL-C) levels in this model. For 30 days, male hamsters were fed a cholesterol-rich cereal-based diet containing either a submaximal dose of cholestyramine (1% wt/wt) alone or in combination with psyllium (either 2 or 4%), or a high dose of cholestyramine (3%) alone. Although the greatest cholesterol-reducing action was achieved with 3% resin alone, in the animals fed one third as much cholestyramine combined with psyllium (4%) LDL-C production decreased from 288 +/- 15 to 187 +/- 17 micrograms/h per 100 g body weight, the suppression of LDL-receptor activity was almost fully reversed, plasma LDL-C levels were reduced from 90 +/- 8 to 41 +/- 5 mg/dl, and hepatic cholesterol content decreased from 17.1 +/- 1.9 to 2.4 +/- 0.1 mg/g. In the group that received 1% resin alone, the plasma LDL-C and hepatic cholesterol levels were 60 +/- 3 mg/dl and 7.2 +/- 0.6 mg/g, respectively. As compared with animals that received 1% resin alone, those fed both agents manifested higher rates of fecal bile acid excretion and lower levels of intestinal cholesterol absorption. A significant cholesterol-lowering benefit can be derived from using these nonsystemic agents in combination at lower, more tolerable doses.

Animals↗
PubMed1996

Brain does not utilize low density lipoprotein-cholesterol during fetal and neonatal development in the sheep.

Several lines of evidence have suggested that central nervous system development and function depend upon a supply of cholesterol that comes from low density lipoproteins (LDL-C). These studies test this hypothesis directly by measuring in vivo the uptake of LDL-C in nine regions of the central nervous system at five different stages of development in the fetal and neonatal sheep. The concentration of LDL-C in the plasma decreased from 49 mg/dl in the fetus 90 days before birth (-90 days) to only 10 mg/dl at -13 days. By 17 days postnatal this value increased to nearly 60 mg/dl. Throughout the period of development between -90 days (very early fetus) and 17 days (late neonatal animal) the weight of the brain increased 32-fold (from 2.3 to 73.6 g) and the content of cholesterol rose 100-fold (from 8.6 to 876 mg), yet there was no detectable LDL-C uptake in any of nine areas of the central nervous system at any stage of development (clearances of < 2 microliters/h per g). This was true even in the -90 day fetus prior to closure of the blood brain barrier. In contrast, LDL-C clearance by the adrenal gland increased dramatically (from 91 to 348 microliters/h per g) as it also did in the liver (from 36 to 85 microliters/h per g) during fetal development. These studies strongly suggest, therefore, that cholesterol carried in LDL plays little or no role in the process of sterol acquisition during brain development or in cholesterol turnover in the mature central nervous system. Changes in circulating LDL-C concentration, therefore, should have no effect on brain function.

Adrenal Glands↗
PubMed1995

Mechanisms of LDL-cholesterol lowering action of psyllium hydrophillic mucilloid in the hamster.

Psyllium hydrophillic mucilloid (psyllium) is a soluble fiber that significantly lowers plasma low-density lipoprotein (LDL)-cholesterol levels in humans and experimental animals. These studies were designed to determine whether this action is the result of a reduction in LDL-cholesterol production, an increase in receptor-mediated LDL clearance by the tissues, or a combination of these mechanisms. Adult male Golden Syrian hamsters were fed ad libitum for 30 days a cereal-based diet containing added cholesterol (0.1%) and hydrogenated coconut oil (10%), as well as either microcrystalline cellulose (Avicel) (7.5%) or psyllium (7.5%). In contrast to their Avicel-fed controls, the hamsters given psyllium had markedly lower plasma total (122.1 +/- 4.1 vs. 399.4 +/- 39.4 mg/dl) and LDL-cholesterol (46.0 +/- 2.2 vs. 143.5 +/- 12.0 mg/dl) levels. Psyllium feeding also prevented both the dramatic increase in hepatic total cholesterol levels (2.6 +/- 0.1 vs. 16.6 +/- 1.1 mg/g), and the suppression of hepatic cholesterol synthesis (165.1 +/- 27.1 vs. 26.1 +/- 1.2 nmol/h per g) that occurred in the animals given Avicel. Compared to their controls, the psyllium-fed animals also manifested a 44% lower rate of LDL-cholesterol production (167.6 +/- 8.1 vs. 300.2 +/- 16.0 micrograms/h per 100 g bw), and a 2.2-fold higher rate of hepatic LDL clearance (50.1 +/- 2.3 vs. 22.6 +/- 2.1 microliters/h per g). When expressed as a percentage of corresponding values obtained for hamsters fed the basal diet without any additions, the relative rate of LDL-cholesterol production was 175 +/- 10% and 99 +/- 4% for the Avicel- and psyllium-fed groups, respectively. It was similarly determined that the level of whole animal relative LDL receptor activity was marginally higher in the hamsters given psyllium (55.9 +/- 1.4%) than in those fed Avicel (47.5 +/- 3.3%). Thus, it was concluded that while the LDL-cholesterol lowering action of psyllium in the hamster is mediated through two mechanisms, the major effect is exerted at the level of LDL-cholesterol production.

Animals↗
PubMed1995

Sterol metabolism in fetal, newborn, and suckled lambs and their response to cholesterol after weaning.

Several aspects of cholesterol metabolism were studied in lambs at six stages of development. The first three stages involved fetal lambs with gestational ages (fertilization set at -150 days) of -73 days (early fetal), -42 days (midfetal), and -14 days (late fetal). The other groups comprised newborn (0 days), suckled (17 days), and weaned (105 days) lambs. The liver, kidney, spleen, and brain actively synthesized cholesterol at all stages of development, but hepatic synthesis in the suckled lambs was markedly suppressed compared with that in their newborn and weaned counterparts. Whereas intestinal sterol synthesis was very low in all the fetal lambs, the converse was true in the neonatal animals. The total cholesterol concentration in the liver, intestine, kidney, and spleen remained relatively constant at all stages of growth, whereas in brain tissue it increased throughout development. Plasma total and low-density-lipoprotein cholesterol levels were lowest in the late fetal lambs and highest in the suckled animals. The metabolic response of weaned lambs to a dietary cholesterol challenge was similar to that reported for various monogastric species.

Animals↗
PubMed1995

Role of liver in the synthesis of cholesterol and the clearance of low density lipoproteins in the cynomolgus monkey.

The suitability of the adult male cynomolgus monkey as a model for investigating genetic mechanisms that regulate dietary cholesterolemic response was evaluated by carrying out a systematic characterization of the major aspects of cholesterol metabolism in this species. In monkeys maintained on a diet enriched with saturated fat but low in cholesterol (0.019%, wt/wt), plasma total and low density lipoprotein cholesterol (LDL-C) concentrations were 118 +/- 6 and 45.3 +/- 3.4 mg/dl, respectively. Intestinal cholesterol absorption averaged 54.0 +/- 2.5%, and the rate of whole body sterol synthesis was 10.8 +/- 0.6 mg/day per kg body weight. Only 11.2 +/- 2.6% of this synthesis occurred in the liver. In contrast, the liver was the major site for low density lipoprotein clearance accounting for almost 80% of LDL-C degradation in these animals. The liver, which represented 1.5% of whole body mass, had a total and esterified cholesterol concentration of 4.95 +/- 0.29 and 2.05 +/- 0.30 mg/g, respectively. When challenged with a matching high cholesterol diet (0.19%, wt/wt), the monkeys developed marked hypercholesterolemia that was accounted for mainly by a 7-fold increase in the LDL-C levels. There was, however, wide individual variation among the monkeys in the magnitude of their cholesterolemic response. Hepatic total and esterified cholesterol levels increased 2.5- and 4.6-fold, respectively. Comparative experiments showed that while several of the metabolic characteristics of this species of monkey were similar to those found in the hamster, they were generally very different from those seen in the rat. Thus, the male cynomolgus monkey has many characteristics in common with humans and represents an attractive model for further delineating the genetic mechanisms that dictate variable responsiveness to dietary cholesterol and triacylglycerol.

Animals↗