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Biomedical subjects

S D Turley

Publications and source records attributed to S D Turley.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1994

Psyllium augments the cholesterol-lowering action of cholestyramine in hamsters by enhancing sterol loss from the liver.

BACKGROUND/AIMS: Psyllium hydrophilic mucilloid is a nonabsorbable soluble fiber that lowers plasma cholesterol levels in several species, including humans. However, its mechanism of action has not been fully elucidated. Therefore, using a hamster model, experiments were performed to determine whether psyllium given alone or in combination with a submaximal dose of cholestyramine blocks intestinal cholesterol absorption. METHODS: The efficiency of cholesterol absorption and concentrations of plasma and hepatic total cholesterol were measured in male hamsters fed a cholesterol-enriched chow diet (0.1%) that contained either avicel (cellulose) (7.5%), surfomer (3%), cholestyramine (1% or 3%), or psyllium (7.5%) as single agents or a fixed level of cholestyramine (1%) combined with variable levels of psyllium (2%, 4%, 6%, or 8%). RESULTS: Psyllium, cholestyramine, and surfomer, when given alone, markedly lowered plasma and hepatic cholesterol concentrations. Surfomer, and cholestyramine at the higher dose (3%), blocked cholesterol absorption by 54% and 75%, respectively, whereas psyllium had no effect. Combining psyllium with a submaximal dose of cholestyramine augmented the cholesterol-lowering action of the resin without effecting any marked change in the level of cholesterol absorption, except at the highest dose used. CONCLUSIONS: Psyllium, given either as a single agent or as an adjunct to treatment with cholestyramine, exerts a significant hypocholesterolemic effect by enhancing net negative sterol balance across the liver.

Animals↗
PubMed1994

Reevaluation and application of the dual-isotope plasma ratio method for the measurement of intestinal cholesterol absorption in the hamster.

These experiments systematically evaluated the dual-isotope plasma ratio method for measuring intestinal cholesterol absorption in the hamster. It was found that while the ratio of the 3H- and 14C-labeled cholesterol in the plasma, relative to the respective dose of each that was given, became constant by 72 h after their administration, the percent cholesterol absorption was lower in animals that were fasted before dosing (35.7 +/- 5.5%) than in their fed controls (47.5 +/- 3.7%). Furthermore, the percent absorption found 72 h after dosing varied greatly, depending on whether the intragastric dose of labeled cholesterol was administered in medium chain triglyceride (MCT) oil (46.2 +/- 2.3%), olive oil (63.9 +/- 11.2%), or safflower oil (74.6 +/- 4.5%). The level of absorption was not different between hamsters that had unrestricted (46.3 +/- 1.6%) and restricted (43.8 +/- 2.2%) access to their stools during the 72 h after dosing. Other experiments, using only hamsters in the fed state and MCT oil as the intragastric dosing medium, showed that the percent cholesterol absorption could be made to vary over a wide range using treatments known to produce such effects in humans. Thus, feeding either surfomer, cholestyramine, ursodeoxycholic acid, or CI-976, a new inhibitor of acyl-CoA:cholesterol acyltransferase, significantly blocked cholesterol absorption, whereas the addition of either cholic acid or increasing amounts of oil to the diet had the opposite effect. The modified dual-isotope plasma ratio method described here provides a simpler and more physiologic approach to the routine measurement of cholesterol absorption in the hamster and similar small animal models.

Administration, Oral↗
PubMed1991

Cholesterol-lowering action of psyllium mucilloid in the hamster: sites and possible mechanisms of action.

These studies were undertaken to examine and compare the metabolic effects of psyllium mucilloid and two other nonabsorbable polymers (cholestyramine and surfomer) on sterol metabolism in the hamster. These three agents all significantly lowered the plasma total cholesterol concentration and the level of cholesterol carried in low-density lipoproteins (LDL). Rates of cholesterol synthesis were markedly increased in the livers of the psyllium-fed animals, but not in other tissues. In contrast, cholestyramine and surfomer feeding increased both hepatic and intestinal sterol synthesis. When cholesterol and saturated triacylglycerols were added to the diet, psyllium feeding essentially completely blocked the increase in the plasma cholesterol concentration and hepatic cholesterol content and the suppression of cholesterol synthesis. The pool of bile acid in the small intestine was increased from the control value (17.9 mumol/animal) by both psyllium (23.0 mumol) and cholestyramine (21.9 mumol) feeding. However, this pool was readily absorbed and secreted into the bile in the psyllium-fed animals (27.9 mumol/4 h), but not in the cholestyramine-treated hamsters (13.0 mumol/4 h). This was consistent with the further observation that there was no binding of bile acid by psyllium under in vitro conditions. Thus, these findings indicate that all three polymers lower plasma cholesterol concentrations by inducing a net negative cholesterol balance across the liver. With psyllium, this effect is presumably articulated through a reduction in cholesterol absorption, as well as an increase in the rate of degradation of cholesterol to bile acids.

Animal Feed↗
PubMed1988

Regulation of bile acid pool size and plasma lipid levels in the SHR/N-corpulent rat: influence of the level of caloric intake.

In the obese progeny of the SHR/N-cp strain of the rat the bile acid pool was at least twice as large as that in their lean littermates even when only 6 weeks old. The composition of the pool remained unchanged in the obese females, but in their male counterparts the proportion of cholic acid was significantly increased. Cholestyramine feeding reduced the pool size by 26% in the obese rats, but a similar effect also occurred in the lean animals. The obese rats consumed about 60% more food per day than their lean littermates. When obese females were pair-fed to the intake of their lean controls from 6 to 11 weeks of age, the bile acid pool remained significantly enlarged, although not to the same extent as in the obese rats fed ad lib. Plasma cholesterol levels were reduced but remained significantly higher than the levels in the lean animals. The marked hypertriglyceridemia exhibited by the obese rats fed ad libitum did not develop in their pair-fed counterparts. In contrast, there was a comparatively smaller reduction in plasma cholesterol and triglyceride levels in the obese rats fed cholestyramine. Hepatic steatosis persisted in the pair-fed animals as well as in those given cholestyramine. Restricting caloric intake significantly reduced the body weight gain of the obese rats but had little effect on the extent of their corpulence. These studies show that at least some of the characteristics of this congenic strain, including hypertriglyceridemia and hepatic and intestinal hypertrophy, are due mainly to excess dietary intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Metabolism of high-density lipoprotein in the hyperlipidemic, diabetic SHR/N-corpulent rat.

The SHR/N-corpulent rat is a new genetically obese strain that is both hyperlipidemic and diabetic. The high density lipoprotein (HDL) fraction from 12-week-old obese males contained significantly greater amounts of protein (+83%), free (+72%) and esterified (+76%) cholesterol, phospholipid (+94%), and triglyceride (+78%). HDL from obese rats were also enriched in C apolipoproteins (apo C-III0 and apo C-III3) but had similar relative amounts of both apo A-I and apo E compared to HDL from their lean littermates. HDL protein turnover, measured with 125I-labeled HDL, showed that obese rats had a smaller fractional catabolic rate (FCR) than lean rats, but due to their much larger HDL pool size, they had a significantly higher rate of HDL protein catabolism (obese, 1.98 +/- 0.07 mg/whole animal/h v lean, 1.32 +/- 0.05 mg/whole animal/h). Therefore, under steady-state conditions, HDL protein production must also have been increased in the obese animals. To determine whether the increased catabolism of HDL protein was associated with increased catabolism of cholesteryl ester (CE), tissue uptake of HDL CE was measured using the nonhydrolyzable ether analogue [3H]cholesteryl linoleyl ether. After four hours 41.6 +/- 1.6% of the injected dose was cleared from the plasma of lean rats compared with 37.0 +/- 1.1% from the plasma of obese rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Disproportional changes in the rates of biliary bile acid, phospholipid and cholesterol secretion in the SHR/N-corpulent rat.

Lean and obese male rats of the SHR/N-cp strain were fed a plain chow diet ad libitum and studied at 11-13 weeks of age. Compared to their lean littermates the obese animals manifested 2-4-fold higher plasma levels of cholesterol, triacylglycerol and glucose. In the obese rats, the mass of the liver was increased more than 70% and there was a significant increase in the total hepatic content of free cholesterol (42%), cholesteryl ester (2.9-fold) and triacylglycerol (7.4-fold). Despite the difference in liver mass, the rate of bile secretion was the same in the lean and obese groups. Bile acid pool size was 2.5-fold greater in the obese rats and this was reflected in an enhanced rate of biliary bile acid secretion. In contrast, there was little or no increase in biliary cholesterol and phospholipid secretion, so the relative content (molar percentage) of these lipids decreased significantly in the obese animals. In both the lean and obese groups, biliary cholesterol and phospholipid output could be enhanced by the intravenous administration of taurocholate, but the proportion of both lipids in the bile of the obese rats remained significantly lower than in their lean controls. Thus the difference in biliary lipid composition between the two groups is not due to a limited availability of cholesterol and phospholipid for transport into bile, but more likely reflects a difference in the reaction whereby the secretion of cholesterol and phospholipid is coupled to the transport of bile acids across the canalicular membrane.

Animals↗
PubMed1986

Rates of sterol synthesis in the liver and extrahepatic tissues of the SHR/N-corpulent rat, an animal with hyperlipidemia and insulin-independent diabetes.

The SHR/N-corpulent rat is a new genetically obese strain that exhibits both insulin-independent diabetes and hyperlipidemia. The present studies were undertaken to characterize various parameters of cholesterol metabolism in this model. At 11 weeks of age, the obese animals had markedly elevated plasma cholesterol, triglyceride, glucose, and insulin concentrations and elevated hepatic triglyceride concentrations compared to their lean littermates. The additional cholesterol in plasma was carried in the fractions of density less than 1.006, 1.020-1.055, 1.055-1.095, and 1.095-1.21 g/ml. In the obese rats the level of free cholesterol in the liver was decreased significantly while that of cholesteryl ester showed little change. Hepatic sterol synthesis was markedly suppressed in the obese animals. However, the rate of sterol synthesis in the small intestine and other extrahepatic tissues generally remained unchanged. Although hepatic synthesis was suppressed, whole animal sterol synthesis in the obese rats was similar to that in the lean controls. This resulted because, in the obese animals, not only was the reduced rate of hepatic synthesis partly balanced by a greater than 70% increase in liver mass, but the mass of the small intestine and adipose tissue was also increased more than 30% and 4-fold, respectively, thereby making these tissues quantitatively more important sites of sterol synthesis. When obese rats were pair-fed to the intake of their lean littermates for 10 weeks, there was only a modest reduction in body weight and plasma cholesterol concentration, and the rate of hepatic sterol synthesis remained very low. The suppression of synthesis in the liver also persisted when the obese rats were fed surfomer, a drug that specifically blocks cholesterol absorption. In contrast, feeding cholestyramine restored the rate of hepatic sterol synthesis to that found in lean animals. Bile acid pool size in the obese males and females was 2.5-fold greater than in their lean controls. The suppression of hepatic sterol synthesis in this model may be due to a change in the entero-hepatic circulation of bile acids arising from an expanded pool or, alternatively, it may represent a compensatory response to overproduction of sterol and its precursors in the intestinal and adipose compartments.

Adipose Tissue↗