Biomedical subjects

D K Spady

Publications and source records attributed to D K Spady.

At least 19 recordsLinked to original sources

PubMed1998

Overexpression of cholesterol 7alpha-hydroxylase (CYP7A) in mice lacking the low density lipoprotein (LDL) receptor gene. LDL transport and plasma LDL concentrations are reduced.

This study was undertaken to determine the effect of transient overexpression of hepatic cholesterol 7alpha-hydroxylase on low density lipoprotein (LDL) cholesterol transport in mice lacking LDL receptors (LDL receptor-/-). Primary overexpression of hepatic 7alpha-hydroxylase in LDL receptor-/- mice was accompanied by a dose-dependent decrease in the rate of LDL cholesterol appearance in plasma (whole body LDL cholesterol transport) and a corresponding reduction in circulating LDL cholesterol levels. The increase in hepatic 7alpha-hydroxylase activity necessary to achieve a 50% reduction in plasma LDL cholesterol concentrations was approximately 10-fold. In comparison, cholestyramine increased hepatic 7alpha-hydroxylase activity approximately 3-fold and reduced plasma LDL cholesterol concentrations by 17%. This study demonstrates that augmentation of hepatic 7alpha-hydroxylase expression is an effective strategy for lowering plasma LDL concentrations even in animals with a genetic absence of LDL receptors.

Animals↗

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

Kinetic characteristics and regulation of HDL cholesteryl ester and apolipoprotein transport in the apoA-I-/- mouse.

The concentration dependence and tissue distribution of high density lipoprotein (HDL) cholesteryl ester and apolipoprotein (apo) transport were determined in apoA-I knockout mice (apoA-I-/-) that lack normal HDL in plasma. Rates of HDL cholesteryl ester clearance were highly sensitive to plasma HDL cholesteryl ester concentrations with clearance rates falling by 80% in the liver and by 95% in the adrenal glands when plasma HDL cholesteryl ester concentrations were acutely raised to levels normally seen in control mice (approximately 50 mg/dl). With the exception of the brain, saturable HDL cholesteryl ester uptake was demonstrated in all tissues of the body, with the adrenal glands and liver manifesting the highest maximal transport rates (Jm). The plasma concentration of HDL cholesteryl ester necessary to achieve half-maximal transport (Km) equaled 4 mg/dl in the adrenal glands and liver; as a consequence, HDL cholesteryl ester uptake by these organs is maximal (saturated) at normal plasma HDL concentrations in the mouse. When expressed per whole organ, the liver was the most important site of HDL cholesteryl ester clearance accounting for approximately 72% of total HDL cholesteryl ester turnover at normal plasma HDL concentrations. HDL cholesteryl ester transporter activity and scavenger receptor type B1 (SR-BI) protein and mRNA levels were not up-regulated in any organ of apoA-I-/- mice even though these animals lack normal HDL.

Animals↗

PubMed1997

Kinetic parameters for high density lipoprotein apoprotein AI and cholesteryl ester transport in the hamster.

These studies were undertaken to determine the kinetic characteristics of high density lipoprotein (HDL) apo AI and cholesteryl ester transport in the hamster in vivo. Saturable HDL apo AI transport was demonstrated in the kidneys, adrenal glands, and liver. Saturable HDL cholesteryl ester transport was highest in the adrenal glands and liver. In the liver and adrenal glands, maximal transport rates (J(m)) for receptor dependent uptake were similar for the protein and cholesteryl ester moieties; however, the concentration of HDL necessary to achieve half-maximal transport (K(m)) was 20- to 30-fold higher for apo AI. Consequently, at normal plasma HDL concentrations, the clearance of HDL cholesteryl ester exceeded that of HDL apo AI by approximately 10-fold in the adrenal glands and by approximately fivefold in the liver. At normal HDL concentrations, the majority of HDL cholesteryl ester (76%) was cleared by the liver whereas the majority of HDL apo AI (77%) was cleared by extrahepatic tissues. The rate of HDL cholesteryl ester uptake by the liver equaled the rate of cholesterol acquisition by all extrahepatic tissues suggesting that HDL cholesteryl ester uptake by the liver accurately reflects the rate of "reverse cholesterol transport." Receptor dependent HDL cholesteryl ester uptake by the liver was maximal (saturated) at normal plasma HDL concentrations. Consequently, changes in plasma HDL concentrations are not accompanied by parallel changes in the delivery of HDL cholesteryl ester to the liver unless the number or affinity of transporters is also regulated.

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↗

PubMed1997

Diet modification alters plasma HDL cholesterol concentrations but not the transport of HDL cholesteryl esters to the liver in the hamster.

These studies were undertaken to investigate the mechanism whereby diet modification alters the plasma concentration of high density lipoprotein (HDL) cholesteryl ester and apoA-I and to determine whether diet-induced alterations in circulating HDL levels are associated with changes in the rate of reverse cholesterol transport. Rates of HDL cholesteryl ester and apoA-I transport were measured in hamsters fed a control low-cholesterol, low-fat diet or the same diet supplemented with soluble fiber (psyllium) or with cholesterol and triglyceride (Western-type diet). The Western-type diet increased the plasma concentration of HDL cholesteryl ester by 46% compared to the control diet and by 86% compared to the psyllium-supplemented diet; nevertheless, the absolute rates of HDL cholesteryl ester transport to the liver were identical in the three groups. Diet-induced alterations in circulating HDL cholesteryl ester levels were due to changes in the rate of HDL cholesteryl ester entry into HDL (whole body HDL cholesteryl ester transport) and not to regulation of HDL cholesteryl ester clearance mechanisms. The Western-type diet increased the plasma concentration of HDL apoA-I by 25% compared to the control diet and by 45% relative to the psyllium-supplemented diet. Diet-induced alterations in plasma HDL apoA-I concentrations were also due entirely to changes in the rate of apoA-I entry into HDL (whole body HDL apoA-I transport). These studies demonstrate that the absolute flux of HDL cholesteryl ester to the liver, which reflects the rate of reverse cholesterol transport, remains constant under conditions in which plasma HDL cholesteryl ester concentrations are altered over a nearly 2-fold range by diet modification.

Animals↗

PubMed1996

Feedback regulation of hepatic 7alpha-hydroxylase expression by bile salts in the hamster.

Hepatic 7alpha-hydroxylase activity appears to be regulated at the transcriptional level by the quantity of bile salts fluxing through the enterohepatic circulation. Whether bile salts directly suppress 7alpha-hydroxylase expression at the level of the hepatocyte or do so indirectly by promoting the release or absorption of an intestinal factor has not been resolved. We have investigated the ability of primary bile salts to suppress hepatic 7alpha-hydroxylase expression in bile-diverted hamsters. Biliary diversion was accompanied by derepression of both hepatic 7alpha-hydroxylase activity (4-5-fold) and bile salt secretion (approximately 3-fold). Derepression of hepatic 7alpha-hydroxylase expression could be prevented by several interventions that increase the availability of bile salts within the hepatocyte including 1) overexpression of an exogenous 7alpha-hydroxylase gene by adenovirus-mediated gene transfer, 2) obstruction of the common bile duct, and 3) intravenous infusions of taurocholate. In contrast, none of these interventions prevented derepression of hepatic cholesterol synthesis or significantly down-regulated hepatic low density lipoprotein receptor expression over the relatively short time course (24 h) of these studies. Together, these data indicate that primary bile salts contribute to the regulation of bile salt synthesis through feedback repression of 7alpha-hydroxylase expression at the level of the hepatocyte.

Adenoviridae↗

PubMed1996

Effect of hypocholesterolemic doses of 17 alpha-ethinyl estradiol on cholesterol balance in liver and extrahepatic tissues.

This study was performed to investigate the effects of 17 alpha-ethinyl estradiol, a potent hypocholesterolemic agent at pharmacological doses, on cholesterol balance in the liver and extrahepatic tissues of the rat in vivo. Female Sprague-Dawley rats were treated with 17 alpha-ethinyl estradiol (5 mg/kg per day s.c. for 5 days) or with 4-aminopyrazolo(3,4-d) pyrimidine (20 mg/kg per day i.p. for 3 days). Both drug regimens suppressed plasma total and low density lipoprotein-cholesterol by more than 80%. Analysis of the kinetic parameters of low density lipoprotein transport did not show increased receptor activity in extrahepatic tissues during either treatment. 17 alpha-Ethinyl estradiol significantly increased low density lipoprotein tissue spaces and clearance rates in the liver, with a 5-fold increase in low density lipoprotein-receptor activity, whereas 4-aminopyrazolo(3,4-d)pyrimidine suppressed hepatic transport of low density lipoprotein probably due to a nospecific toxic effect. Treatment with 17 alpha-ethinyl estradiol markedly enhanced the hepatic expression of low density lipoprotein-receptor protein and mRNA despite a 7-fold increase in hepatic cholesteryl ester levels. Finally, treatment with both drugs increased cholesterol synthesis in several extrahepatic tissues, such as adrenals, ovaries, small bowel, and spleen. These findings confirm that 17 alpha-ethinyl estradiol at pharmacological doses markedly increases synthesis and expression of low density lipoprotein-receptor in the liver. Hypocholesterolemia, whether induced by activation of low density lipoprotein-receptors or by other mechanisms, fails to up-regulate low density lipoprotein transport in extrahepatic tissues, which rather respond by increasing local sterol synthesis. This suggests the occurrence of separate regulatory mechanisms for low density lipoprotein transport and cholesterol synthesis.

Adenine↗

PubMed1996

Endotoxin, TNF, and IL-1 decrease cholesterol 7 alpha-hydroxylase mRNA levels and activity.

Endotoxin (LPS) and cytokines increase cholesterol synthesis and the secretion of lipoproteins by the liver in rodents resulting in hypercholesterolemia. Cholesterol 7 alpha-hydroxylase (CAH) is the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver, the major regulated pathway by which cholesterol is eliminated from the body. Decreases in CAH would increase the quantity of cholesterol available for lipoprotein production. In the present study, we demonstrate that LPS, TNF, or IL-1 administration to Syrian hamsters produces a marked decrease in the levels of CAH mRNA in the liver. This marked decrease occurred even when the basal level of CAH expression was increased by feeding the bile acid sequestrant, colestipol. Additionally, a marked decrease was also observed when the animals were fed a cholesterol-enriched diet. Moreover, the decrease in CAH mRNA occurred very rapidly (decreased 66% by 90 min after LPS administration) and required relatively small doses of LPS (100 ng/100 g body weight). Lastly, the decrease in mRNA levels was accompanied by a decrease in CAH activity. This decrease in CAH could contribute to the increase in hepatic lipoprotein production induced by LPS and cytokines. CAH can be added to the growing list of proteins that regulate lipid metabolism and that are altered during the acute phase response.

Animals↗

PubMed1995

Regulation of hepatic cholesterol metabolism in the rat in vivo: effect of a synthetic fat-free diet on sterol synthesis and low-density lipoprotein transport.

A synthetic fat-free diet, previously shown to decrease hepatic cholesterol synthesis, was utilized to manipulate cholesterol balance in vivo in female Sprague-Dawley rats. A significant 65% decrease of hepatic cholesterol synthesis compared to controls was shown after 1 week of treatment, which remained constant during the following 3 weeks. The inhibitory effect of the diet was completely abolished by cholestyramine supplementation. At week 3 of the experimental diet, bile acid synthesis was reduced by 63%, this reduction being correlated with decreased recycling frequency of the bile acid pool. Hepatic clearance of low-density lipoprotein (LDL) was slightly decreased, with no changes in plasma cholesterol, hepatic LDL-cholesterol uptake and whole body LDL-cholesterol production. When cholesterol and saturated fatty acids were supplemented to the diets in the attempt to disclose alteration in LDL transport, LDL clearance was unaffected; plasma LDL-cholesterol and hepatic LDL-cholesterol uptake were increased, as a consequence of increased LDL-cholesterol production. On the other hand, hepatic cholesterol synthesis was further suppressed; bile acid synthesis was increased by cholesterol supplementation in the fat-free group, even if to subnormal levels. These findings suggest that: (1) bile acid synthesis is decreased by feeding a synthetic fat-free diet, probably due to slower recirculation of bile acids along the entero-hepatic axis in conditions of reduced functional need; (2) consequently, a significant reduction of hepatic cholesterol synthesis is observed with no changes in LDL-cholesterol uptake; (3) further supplementation of dietary cholesterol and saturated fats is compensated for by changes in the rates of cholesterol and bile acid synthesis, but not of LDL transport. The data confirm the existence of independent regulation for hepatic sterol synthesis and LDL transport in this species.

Animals↗

PubMed1995

Regulation of hepatic 7 alpha-hydroxylase expression and response to dietary cholesterol in the rat and hamster.

Although dietary cholesterol raises plasma total and low density lipoprotein (LDL) cholesterol concentrations, the response to a given intake of cholesterol varies enormously among different species and even among individuals of the same species. The mechanisms responsible for differing sensitivity to dietary cholesterol were examined by comparing the rat, which is able to adapt to large fluctuations in sterol intake or loss with little change in plasma LDL levels, with the hamster, where changes in sterol balance strongly influence plasma LDL concentrations. When fed the same cholesterol-free diet, hepatic 7 alpha-hydroxylase activity was 16-fold higher in the rat than in the hamster. As a consequence, rates of hepatic cholesterol synthesis were 20-fold higher in the rat than in the hamster. In both species, hepatic cholesterol synthesis was suppressed > 90% in response to increasing loads of dietary cholesterol. However, the quantitative importance of this adaptive mechanism was much greater in the rat since the absolute reduction in hepatic cholesterol synthesis in the rat (2,110 nmol/h/g) was much larger than in the hamster (103 nmol/h/g). In the rat, the high basal level of 7 alpha-hydroxylase expression was further induced by substrate (cholesterol) allowing these animals to convert excess dietary cholesterol to bile acids efficiently. In contrast, the low basal level of enzyme expression in the hamster was not induced by dietary cholesterol. Thus, the low basal rates of bile acid and cholesterol synthesis coupled with a lack of 7 alpha-hydroxylase induction by cholesterol render the hamster much more sensitive than the rat to the cholesterolemic effects of dietary cholesterol.

Animals↗

PubMed1995

Adenovirus-mediated transfer of a gene encoding cholesterol 7 alpha-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol.

Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7 alpha-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7 alpha-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMV7 alpha). Syrian hamsters administered AdCMV7 alpha intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7 alpha-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7 alpha-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by approximately 60% in animals maintained on control diet and by approximately 75% in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7 alpha-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk.

Adenoviridae↗

PubMed1995

Regulatory effects of n-3 polyunsaturated fatty acids on hepatic LDL uptake in the hamster and rat.

These studies were undertaken to investigate the mechanisms involved in the regulation of hepatic low density lipoprotein (LDL) transport by n-3 fatty acids in the hamster and rat. Animals were fed n-3 or n-6 fatty acids with a cholesterol-free, very-low-fat semisynthetic diet, or with a diet enriched with cholesterol and saturated fat. Although the enrichment of liver lipids with dietary n-3 fatty acids was similar in hamsters and rats, the effect of n-3 fatty acids on hepatic LDL transport differed in the two species. In the hamster, n-3 fatty acids had no effect on hepatic receptor-dependent LDL uptake in animals fed a cholesterol-free, very-low-fat diet and suppressed receptor-dependent transport in animals fed a diet enriched with cholesterol and saturated triglyceride. In hamsters fed n-3 fatty acids, changes in receptor-dependent LDL transport were accompanied by parallel changes in LDL receptor mRNA, indicating regulation of the receptor at the pretranslational level. In the rat, on the other hand, dietary n-3 fatty acids enhanced hepatic receptor-dependent LDL uptake by nearly twofold regardless of the background diet; however, hepatic LDL receptor protein and mRNA were unchanged. Dietary n-3 fatty acids did not enhance hepatic chylomicron remnant clearance in the rat. These studies confirm marked species differences in response to n-3 fatty acids and suggest that n-3 fatty acids accelerate hepatic receptor-dependent LDL transport in the rat by altering the distribution or recycling of LDL receptors or via effects on a different receptor pathway.

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

Regulation of hepatic 7 alpha-hydroxylase expression by dietary psyllium in the hamster.

Soluble fiber consistently lowers plasma total and low density lipoprotein (LDL)-cholesterol concentrations in humans and various animal models including the hamster; however, the mechanism of this effect remains incompletely defined. We performed studies to determine the activity of dietary psyllium on hepatic 7 alpha-hydroxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and LDL receptor expression in the hamster. In animals fed a cholesterol-free semisynthetic diet containing 7.5% cellulose (avicel) as a fiber source, substitution of psyllium for avicel increased hepatic 7 alpha-hydroxylase activity and mRNA levels by 3-4-fold. Comparable effects on 7 alpha-hydroxylase expression were observed with 1% cholestyramine. Psyllium also increased hepatic 7 alpha-hydroxylase activity and mRNA in animals fed a diet enriched with cholesterol and triglyceride. Activation of 7 alpha-hydroxylase was associated with an increase in hepatic cholesterol synthesis that was apparently not fully compensatory since the cholesterol content of the liver declined. Although dietary psyllium did not increase hepatic LDL receptor expression in animals fed the cholesterol-free, very-low-fat diet, it did increase (or at least restore) receptor expression that had been downregulated by dietary cholesterol and triglyceride. Thus, 7.5% dietary psyllium produced effects on hepatic 7 alpha-hydroxylase and LDL metabolism that were similar to those of 1% cholestyramine. Induction of hepatic 7 alpha-hydroxylase activity by dietary psyllium may account, in large part, for the hypocholesterolemic effect of this soluble fiber.

Animals↗

PubMed1993

The interaction of dietary cholesterol and specific fatty acids in the regulation of LDL receptor activity and plasma LDL-cholesterol concentrations.

From these brief considerations, it is clear that the steady-state LDL-cholesterol concentration is determined in a powerful way by the interaction of dietary cholesterol and specific fatty acids. There appear to be only a few saturated fatty acids and an even lesser number of unsaturated fatty acids that significantly interact with cholesterol in the liver cell to alter hepatic LDL receptor activity. These effects are uniformly seen in most experimental animals and in humans under circumstances where the experiments are properly designed. Future work is urgently needed to define the metabolic effects of the more unusual fatty acids (e.g., the trans fatty acid) and the more intimate details of how these substances regulate LDL receptor activity in the cell. It is also of considerable importance to extend these studies to the members of the same species that exhibit variable responses to these same dietary lipids. It is now clear that the magnitude of these specific responses to dietary cholesterol and specific fatty acids varies in different individuals with different genetic backgrounds from the same species. Elucidating the reasons for this variability is another area of research of considerable importance to human biology.

Animals↗

PubMed1993

Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids.

Extensive data obtained in both experimental animals and humans demonstrate that steady-state plasma LDL-C concentrations are determined largely by the rate of LDL-C formation, Jt, and the level of LDL-R activity, Jm, located primarily in the liver. An increase in net cholesterol delivery to the liver suppresses Jm, slightly elevates Jt, and modestly raises the LDL-C level. Feeding lipids such as the 12:0, 14:0, and 16:0 saturated fatty acids further suppresses Jm, increases Jt, and markedly elevates the plasma LDL-C concentration. Feeding triacylglycerols containing the 18:1(c9) fatty acid restores hepatic receptor activity, decreases Jt, and modestly reduces the concentration of LDL-C in the plasma. The 18:2(c9, c12) compound has similar effects, although it is quantitatively less active than the monounsaturated fatty acid in restoring Jm. In contrast to these fatty acids that actively raise or lower hepatic receptor activity, a large group of compounds including the 4:0, 6:0, 8:0, 10:0, 18:0, and 18:1(t9) fatty acids have no demonstrable effect on any parameter of LDL-C metabolism. These fatty acids, therefore, can be added to animal and human diets with relative impunity. They will alter plasma LDL-C levels only to the extent that they replace the active saturated fatty acids (in which case they lower the LDL-C concentration) or unsaturated compounds (in which case they raise the plasma cholesterol level). All of these effects of cholesterol and the various fatty acids can be explained by the effects of these lipids in altering the size of the regulatory pool of cholesterol in the hepatocyte. However, many aspects of the cellular and molecular biology of these regulatory processes require additional investigation. In particular, new studies should focus on how the genetic background of an individual animal or human alters the quantitative response of its plasma LDL-C concentration to the dietary challenge of each of these types of lipids.

Animals↗