Biomedical subjects

J M Dietschy

Publications and source records attributed to J M Dietschy.

At least 73 records · Page 4Linked to original sources

PubMed1987

Role of receptor-independent low density lipoprotein transport in the maintenance of tissue cholesterol balance in the normal and WHHL rabbit.

These studies were undertaken to determine the role of receptor-independent low density lipoprotein (LDL) transport in cholesterol balance across individual tissues and the whole animal. Homologous LDL, which measures total LDL transport, and methylated heterologous LDL, which measures receptor-independent LDL uptake, were cleared from the plasma at very different rates in the NZ control rabbit (3,900 and 1,010 microliter/hr per kg, respectively) whereas in the WHHL rabbit both preparations were cleared at essentially the same rate (approximately 1,070 microliter/hr per kg). Receptor-independent LDL clearance was detected in all tissues of the NZ control rabbit and these varied from 32 (spleen) to less than 0.5 (skeletal muscle) microliter/hr per g. In contrast, receptor-dependent LDL uptake was found in only about half of these same organs. In the WHHL rabbit, the rates of receptor-independent LDL transport were the same as in the NZ control rabbit, but no receptor-dependent uptake was detected. Using these clearance values it was calculated that in the control rabbit nearly 70% of LDL-cholesterol was removed from the plasma by the liver and 89% of this was receptor-mediated. With loss of receptor activity, however, the burden of LDL degradation was shifted away from the liver so that approximately 70% of LDL-cholesterol uptake took place in the extra-hepatic tissues of the WHHL rabbit. Thus, in the normal animal, the primary function of receptor-dependent LDL transport is to promote the rapid uptake and disposal of plasma LDL by the liver. In the absence of such receptor activity, cholesterol balance across most individual organs and the whole animal remains essentially normal and is mediated by the receptor-independent process. Because of the much lower absolute clearance rates manifested by this transport mechanism, however, substantial and predictable elevations in the circulating plasma LDL-cholesterol levels are required to maintain this balance.

Animals↗

PubMed1986

Low density lipoprotein-receptor activity is lost in vivo in malignantly transformed renal tissue.

Mammalian cells can acquire cholesterol through two tightly regulated pathways, namely de novo cholesterol synthesis and receptor-mediated endocytosis of circulating low density lipoprotein (LDL). Malignant cells growing in vitro acquire cholesterol through both mechanisms but the quantitative importance of these pathways to a cancer growing in vivo is not known. Using the Lewis rat renal carcinoma model, this study measured the rate of cholesterol acquisition via both pathways in vivo in both normal and malignant renal tissue. In contrast to normal kidney, after malignant transformation, LDL-receptor activity disappeared entirely and the cancer acquired the cholesterol needed for growth by a 5-fold increase in the rate of cholesterol synthesis.

Adenocarcinoma↗

PubMed1986

Bile acids regulate hepatic low density lipoprotein receptor activity in the hamster by altering cholesterol flux across the liver.

The effect of different bile acids on receptor-dependent and receptor-independent low density lipoprotein (LDL) uptake in the liver and intestine was investigated. When fed at the 0.1% level for three weeks, cholic acid and chenodeoxycholic acid suppressed hepatic cholesterol synthesis in the rat by 80% and 50%, respectively, while ursodeoxycholic acid had no effect. In contrast, hepatic cholesteryl ester levels, rates of hepatic LDL transport, and concentrations of plasma LDL-cholesterol were not affected by bile acid feeding in this species. Cholic acid and chenodeoxycholic acid also suppressed hepatic cholesterol synthesis in the hamster. However, since basal rates of hepatic cholesterol synthesis in this species, as in man, are very low, the absolute reduction in hepatic synthesis could not compensate for the change in hepatic sterol balance induced by bile acid feeding. Hence, in the hamster the feeding of cholic acid and chenodeoxycholic acid increased hepatic cholesteryl ester levels 660% and 39%, respectively, reduced hepatic receptor-dependent LDL uptake by 50% and 32%, respectively, and elevated plasma LDL-cholesterol levels by 160% and 50%, respectively. Ursodeoxycholic acid feeding did not alter any of these processes, and none of the bile acids changed the rate of hepatic receptor-independent LDL transport. In the intestine, none of the bile acids altered rates of cholesterol synthesis or LDL uptake. When cholic acids, chenodeoxycholic acid, or ursodeoxycholic acid was infused continuously for 8 hr in supranormal amounts into control hamsters or rats or into animals pretreated with cholestyramine, there were no changes in LDL transport or any other parameter of hepatic cholesterol metabolism. Thus, these studies indicated that cholic acid and chenodeoxycholic acid have no acute, direct effect on rates of receptor-dependent LDL transport or cholesterol synthesis but do alter these processes indirectly by inducing changes in cholesterol balance across the liver. Ursodeoxycholic acid, in contrast, does not affect these processes either directly or indirectly and so causes no change in plasma LDL levels.

Animals↗

PubMed1986

Measurement of resistance of barriers to solute transport in vivo in rat jejunum.

Assessment of intestinal absorptive function requires techniques for correcting transport constants for diffusion barrier resistance. These studies were done to develop such techniques for use in vivo. In one method the functional thickness of the unstirred water layer (d) in rat jejunum was quantitated electrically, and its minimal surface area (Sw) was measured directly. From these values the diffusion barrier resistance (d/Sw) decreased from 0.041 to 0.022 as the perfusion rate of the intestine was increased from 1.5 to 15 ml/min. In the second method apparent passive permeability coefficients (*P) were measured for a series of saturated fatty acids, and these increased with chain length. However, at the longest chain lengths tested, *P became proportional to their free diffusion coefficients, indicating that uptake was limited by the rate of diffusion up to the microvillus surface. From the rates of uptake of such diffusion-limited probes, the diffusion barrier resistance was again calculated and found to decrease from 0.041 to 0.022 as the rate of perfusion was increased from 1.5 to 15 ml/min. Over this same range of perfusion rates, the apparent Michaelis constant (*Km) for D-glucose transport decreased from 18.2 to 10.0 mM. Using either set of resistance terms and these apparent Km values, the true Km value for glucose transport in vivo was found to equal 0.8 mM when the barrier resistance was extrapolated to zero. Thus these data indicate that diffusion-limited probes can be utilized to measure unstirred layer resistance in the intestine of a live animal so that absolute transport parameters can be determined in vivo in experimental animals and, presumably, in humans.

Animals↗

PubMed1986

Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man.

At the present time the most useful technique with which to examine the kinetics of low-density lipoprotein (LDL) cholesterol in vivo is the labeled LDL turnover study. However, a major limitation of this method is that, despite its ability to accurately measure both the plasma LDL concentration and LDL production rate, it cannot directly quantify LDL receptor activity. The present study defines the equations that describe the relationship between LDL cholesterol production rate, LDL receptor number, and plasma LDL cholesterol concentration. These equations provide a method that allows calculation of total LDL receptor activity based on the results of an LDL turnover study. With the use of this technique and data from previously published series, the effects of the genetic absence of receptors, aging, and the treatment of hypercholesterolemia with mevinolin on LDL cholesterol kinetics were analyzed.

Animals↗

PubMed1986

Kinetic constants for receptor-dependent and receptor-independent low density lipoprotein transport in the tissues of the rat and hamster.

In this study, carried out in the rat and hamster, the receptor-dependent low density lipoprotein (LDL) transport process in each organ was characterized in terms of its maximal uptake rate (Jm) and Michaelis constant (Km), while the rate of receptor-independent uptake was defined in terms of its proportionality constant (P). The highest Jm values of 50-126 micrograms/h per g were found in the liver and endocrine glands in both species and receptor-dependent uptake also was detected in other organs like spleen, kidney, and intestine. The Km values were essentially the same in all of the organs and equaled approximately 90 mg/dl in both species. The receptor-independent uptake constants also were similar in the two species and were highest in the spleen, liver, and intestine. From these values for Jm, Km, and P, it was possible to construct theoretical curves that predict the plasma LDL-cholesterol concentration and fractional catabolic rate given any alteration in LDL-cholesterol production or the magnitude of receptor-dependent LDL transport in any organ of the rat or hamster.

Animals↗

PubMed1986

Renal cell carcinoma in the Wistar-Lewis rat: a model for studying the mechanisms of cholesterol acquisition by a tumor in vivo.

Renal adenocarcinoma implanted into isogeneic Wistar-Lewis rats closely resembles human renal cancer. This paper characterizes the tumor's growth rate, metastatic potential, and its light and electron microscopic appearance. Additionally, for the first time, the pathways through which a tumor acquires the cholesterol needed for growth were quantified in vivo. Two 1-mg pieces of renal carcinoma were implanted beneath the renal capsule of 80 Wistar-Lewis rats. Of the implanted tumors 95% "took" and grew rapidly, doubling every 2.6 days initially. Growth slowed, however, to a doubling time of 8.3 days by the fifth wk. Twenty rats underwent surgical resection of the primary tumor 5 wk after implantation. Of these, 85% subsequently developed lung metastases. Histologically, the tumor had a clear-cell appearance due to the presence of large vacuoles, some of which contained glycogen. The esterified cholesterol content of the tumor was 3-fold higher than normal kidney during the initial period of rapid tumor growth and increased to a 14-fold elevation by 12 wk. The normal kidney in vivo had a high rate of uptake of cholesterol carried in low density lipoproteins and a low rate of de novo sterol synthesis. In contrast, the renal carcinoma lost most of its low density lipoprotein uptake activity and, instead, acquired the cholesterol needed for growth by a 5-fold increase in the rate of de novo cholesterol synthesis. This model may prove valuable in both testing therapeutic strategies directed against human renal cancer and understanding the regulation of cholesterol homeostasis in a growing cancer.

Animals↗

PubMed1985

Rates of cholesterol synthesis and low-density lipoprotein uptake in the adrenal glands of the rat, hamster and rabbit in vivo.

The absolute rate of cholesterol acquisition from de novo synthesis and from receptor-dependent and receptor-independent low-density lipoprotein (LDL) uptake was determined in the adrenal glands of the rat, hamster and rabbit under in vivo conditions. The rate of incorporation of [3H]water into cholesterol in the adrenal gland was much higher in the hamster (1727 nmol/h per g) and rabbit (853 nmol/h per g) than in the rat (71 nmol/h per g). Assuming that 23 atoms of 3H are incorporated into the cholesterol molecule during its biosynthesis, the absolute rates of cholesterol synthesis were then calculated to equal 59, 29 and 2.4 micrograms/h per g of adrenal gland in the hamster, rabbit and rat, respectively. Rates of LDL-cholesterol uptake were measured using a primed continuous infusion of [14C]sucrose-labeled homologous LDL (total LDL transport) and methylated human LDL (receptor-independent LDL transport). The rate of total LDL-cholesterol uptake in the adrenal gland was much higher in the rabbit (227 micrograms/h per g) than in the rat (18 micrograms/h per g) or hamster (6 micrograms/h per g). In all three species LDL uptake was mediated largely (greater than 93%) by receptor-dependent mechanisms. In terms of total cholesterol acquisition, the hamster adrenal gland derived 10-times more cholesterol from de novo synthesis than from LDL uptake, whereas the converse was true in the rabbit. Rates of de novo synthesis and LDL-cholesterol uptake were both low in the rat adrenal gland, which is known to derive cholesterol mainly from circulating high-density lipoproteins. Thus, the adrenal gland acquires cholesterol for hormone synthesis from at least three different sources and the quantitative importance of these sources varies markedly in different animal species, including man.

Adrenal Glands↗

PubMed1985

Dietary saturated triacylglycerols suppress hepatic low density lipoprotein receptor activity in the hamster.

The liver plays a key role in the regulation of circulating levels of low density lipoproteins (LDL) because it is both the site for the production of and the major organ for the degradation of this class of lipoproteins. In this study, the effects of feeding polyunsaturated or saturated triacylglycerols on receptor-dependent and receptor-independent hepatic LDL uptake were measured in vivo in the hamster. In control animals, receptor-dependent LDL transport manifested an apparent Km value of 85 mg/dl (plasma LDL-cholesterol concentration) and reached a maximum transport velocity of 131 micrograms of LDL-cholesterol/hr per g, whereas receptor-independent uptake increased as a linear function of plasma LDL levels. Thus, at normal plasma LDL-cholesterol concentrations, the hepatic clearance rate of LDL equaled 120 and 9 microliter/hr per g by receptor-dependent and receptor-independent mechanisms, respectively. As the plasma LDL-cholesterol was increased, the receptor-dependent (but not the receptor-independent) component declined. When cholesterol (0.12%) alone or in combination with polyunsaturated triacylglycerols was fed for 30 days, receptor-dependent clearance was reduced to 36-42 microliter/hr per g, whereas feeding of cholesterol plus saturated triacylglycerols essentially abolished receptor-dependent LDL uptake (5 microliter/hr per g). When compared to the appropriate kinetic curves, these findings indicated that receptor-mediated LDL transport was suppressed approximately equal to 30% by cholesterol feeding alone and this was unaffected by the addition of polyunsaturated triacylglycerols to the diet. In contrast, receptor-dependent uptake was suppressed approximately equal to 90% by the intake of saturated triacylglycerols. As compared to polyunsaturated triacylglycerols, the intake of saturated lipids was also associated with significantly higher plasma LDL-cholesterol concentrations and lower levels of cholesteryl esters in the liver.

Animals↗

PubMed1985

Effects of specific antibodies, hormones, and lipoproteins on bacterial lipopolysaccharides injected into the rat.

When gram-negative lipopolysaccharides (LPS) are injected intravenously into experimental animals, approximately one-third of the LPS bind to high-density lipoproteins (HDL) in the plasma and are slowly taken up into tissues by HDL-mediated mechanisms. Molecules of LPS in the plasma that do not bind to HDL are taken up more rapidly by tissues that are rich in phagocytic cells (e.g., liver, spleen). In these experiments we evaluated the effects of several potential host factors on the binding of LPS to HDL and on the tissue uptake of LPS injected intravenously into rats. Antibodies to LPS inhibited LPS binding to HDL and increased the uptake of the injected LPS (as well as the LPS in preformed LPS-HDL complexes) by the liver and spleen. High levels of circulating HDL decreased the uptake of injected LPS and LPS-HDL complexes by the adrenal gland, presumably by occupying tissue receptors for HDL. Pretreating rats with dexamethasone unexpectedly decreased the uptake of injected LPS-HDL complexes by the adrenal gland and increased uptake of LPS by the gland, a result suggesting that this drug has opposing effects on the uptake of HDL-bound and -unbound LPS by the adrenal gland. The host factors studied appear to influence the fate of injected LPS by acting at different sites: IgG antibody to LPS blocks the binding of LPS to HDL in the plasma, whereas all of the factors studied have effects that modulate the uptake of LPS or LPS-HDL complexes or both by the cells of specific tissues.

Adrenal Glands↗

PubMed1985

Receptor-independent low density lipoprotein transport in the rat in vivo. Quantitation, characterization, and metabolic consequences.

Receptor-independent low density lipoprotein (LDL) transport plays a critical role in the regulation of plasma cholesterol levels; hence, these studies were done to characterize this process in the tissues of the rat. High rates of receptor-independent clearance were found in the spleen, but other organs, like liver, gastrointestinal tract, and endocrine glands manifested lower clearance rates that varied from 3 to 9 microliter/h per g, while the rates in nervous tissue, muscle, and adipose tissue were less than 1 microliter/h per g. Receptor-dependent uptake was much higher in liver (85 microliter/h per g) and adrenal gland (219 microliter/h per g), but was also low in most other tissues. At normal plasma LDL concentrations, 67% of the receptor-dependent transport in the whole animal was accounted for by LDL uptake in the liver. In contrast, the receptor-independent uptake found in the whole animal took place in many organs, including skeletal muscle (20%), liver (16%), small bowel (15%), skin (10%), and spleen (7%). Furthermore, in liver, the rate of cholesterol synthesis could be varied 11-fold, yet the rate of receptor-independent LDL clearance remained constant at approximately 8 microliter/h per g. When the circulating levels of LDL were systematically increased, receptor-independent LDL clearance also remained constant, so that hepatic LDL-cholesterol uptake by this mechanism increased linearly, from 1 to 20 micrograms/h per g, as the plasma LDL-cholesterol level was increased from 10 to 250 mg/dl. Finally, when equal amounts of LDL-cholesterol were delivered into the liver by either the receptor-dependent or receptor-independent mechanism, there was significant suppression of cholesterol synthesis and an increase in cholesteryl esters. Thus, in any situation in which receptor-dependent LDL degradation is lost, cholesterol balance in the whole animal and across individual organs is maintained by receptor-independent mechanisms, although when the new steady state is achieved, circulating levels of LDL must necessarily be very much increased.

Animals↗

PubMed1985

The origin of cholesterol in the mesenteric lymph of the rat.

These studies were performed to quantitate the amounts of newly synthesized cholesterol secreted in the mesenteric lymph of the rat and to define the origin of this cholesterol. In control animals receiving no dietary fat, the amount of newly synthesized sterol entering the lymph increased linearly with respect to time over 24 hr. When a continuous intravenous infusion of chylomicrons was given or when the animals were prefed a diet containing 2.0% cholesterol to inhibit hepatic, but not intestinal or peripheral, cholesterol synthesis, the secretion of newly synthesized sterol in lymph was markedly suppressed, suggesting that the liver was its ultimate site of origin. When the animals were subjected to either blockade of intestinal cholesterol absorption or biliary diversion, there was a decrease in both the newly synthesized and total mass of cholesterol in lymph by approximately 60%, indicating that the majority was normally derived from the absorption of luminal (primarily biliary) sterol. In the absence of dietary cholesterol, the remainder was probably derived from plasma lipoproteins that were filtered through the intestinal capillaries into the lymph. In contrast, when lymph was collected during active fat absorption, the intestine was found to secrete sterol newly synthesized by the epithelium. Such newly synthesized cholesterol was found predominantly in the unesterified fraction and accounted for approximately 27% of the total sterol found in lymph at the end of the experiment. From these studies it was concluded that in the absence of fat absorption, sterol synthesized in the intestinal mucosa was incorporated predominantly into cell membranes and did not enter intestinal lymph to any significant degree. However, during fat absorption, a fraction of this newly synthesized sterol pool was incorporated into lipoproteins and so was delivered through the intestinal lymph to the body pools of cholesterol.

Animals↗

PubMed1985

Rates of low density lipoprotein uptake and cholesterol synthesis are regulated independently in the liver.

The relationship between rates of hepatic sterol synthesis and rates of hepatic low density lipoprotein (LDL) uptake (clearance) was studied in animals with high (rats), low (female hamsters), and very low (male hamsters) basal rates of hepatic sterol synthesis. In rats and female hamsters, rates of hepatic sterol synthesis were varied over a 110-fold range by feeding cholesterol or cholestyramine; nevertheless, rates of hepatic LDL clearance remained essentially unchanged as did plasma LDL-cholesterol concentrations. In contrast, in male hamsters, which have a very limited capacity to synthesize cholesterol in the liver, cholestyramine feeding increased rates of hepatic LDL uptake by 2.5-fold and this was associated with a 50% reduction in plasma LDL-cholesterol concentrations. The observed increase in LDL uptake was due to an increase in receptor-dependent LDL transport while receptor-independent lipoprotein uptake remained constant. These studies suggest that rates of hepatic cholesterol synthesis and receptor-dependent LDL uptake are regulated independently. Furthermore, the primary response of the liver to changes in cholesterol availability is regulation of sterol synthesis and only when the capacity of this compensatory mechanism is exceeded is the rate of LDL transport altered.

Animals↗

PubMed1984

Measurement of rates of cholesterol synthesis using tritiated water.

Rates of sterol synthesis in various tissues commonly are assessed by assaying levels of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase on isolated microsomes or by measuring the rates of incorporation of various 14C-labeled substrates or [3H]water into cholesterol by whole cell preparations in vitro or by the tissues of the whole animal in vivo. While measurement of activities of HMG-CoA reductase or rates of incorporation of 14C-labeled substrates into cholesterol give useful relative rates of sterol production, neither method yields absolute rates of cholesterol synthesis. The use of [3H]water circumvents the problem of variable and unknown dilution of the specific activity of the precursor pool encountered when 14C-labeled substrates are used and does yield absolute rates of cholesterol synthesis provided that the 3H/C incorporation ratio is known for a particular tissue. In 12 different experimental situations it has been found that from 21 to 27 micrograms atoms of 3H are incorporated into cholesterol from [3H]water in different tissues of several animal species, so that the 3H/C incorporation ratio is similar under nearly all experimental conditions and varies from 0.78 to 1.00. When administered in vivo, [3H]water rapidly equilibrates with intracellular water and is incorporated into sterols within the various organs at rates that are linear with respect to time. From such data it is possible to obtain absolute rates of cholesterol synthesis in the whole animal and in the various organs of the animal. Current data suggest, therefore, that use of [3H]water yields the most accurate rates of cholesterol synthesis both in vitro and in vivo.

Animals↗

PubMed1984

Regulation of cholesterol metabolism in man and in other species.

In the whole animal and in man, cholesterol is acquired either by absorption from the diet or by synthesis in the various organs. While there are marked variations among different animal species, the liver and intestine are generally the most important organs for the synthesis of cholesterol, although recent data indicate that nearly all of the remaining tissues of the body also are capable of significant cholesterol synthesis. Peripheral tissues also acquire cholesterol through the uptake of low density lipoproteins (LDL). However, most LDL are removed from the plasma by the liver, and more than 90% of this clearance process is mediated by the LDL receptor. Hence, the circulating levels of cholesterol carried in LDL are determined primarily by the rate of LDL production and the rate of LDL uptake by the liver. Changes in the rate of entry of cholesterol into the body are compensated for primarily by changes in the rate of cholesterol synthesis in the liver and, to some extent, in the intestine. As long as these changes in synthetic rates can fully compensate for the variations in the rate of cholesterol entry into or exit from the body, the rate of LDL uptake by the liver and the intestine, and the circulating levels of plasma cholesterol, remain essentially constant. When the adaptive changes in cholesterol synthesis are not adequate to meet the changes in cholesterol entry or exit, then the level of LDL receptor activity in the liver may either increase or decrease, resulting in a corresponding lowering or elevation of the circulating plasma LDL-cholesterol levels.

Acetyl Coenzyme A↗

PubMed1984

Regulation of low density lipoprotein uptake and degradation in different animals species.

These various observations suggest that the intestinal-hepatic axis plays a key role in the regulation of cholesterol balance in the whole animal and the circulating levels of LDL-cholesterol. Nearly all sterol which enters or leaves the body must do so through the intestine and liver. Changes in the rate of entry or exit of cholesterol (or bile acids) from the animal are met by appropriate reciprocal changes in the rates of cholesterol synthesis in these two organs. As long as these adaptive changes in synthesis are adequate to meet the changing needs for cholesterol in the animal, the rates of receptor-mediated LDL degradation by the liver and intestine remain essentially unchanged as does the plasma LDL-cholesterol concentration. Only when the changes in cholesterol synthesis are inadequate to meet the changing sterol needs (or are blocked by drug administration (22] does the liver increase its rate of receptor-mediated LDL uptake which, in turn, results in significant alterations in circulating plasma LDL-cholesterol levels.

Animals↗

PubMed1984

Age-related decreases in tissue sterol acquisition are mediated by changes in cholesterol synthesis and not low density lipoprotein uptake in the rat.

The present investigation compared plasma cholesterol levels and lipoprotein profiles, and absolute rates of sterol synthesis and low density lipoprotein (LDL) uptake in various organs of immature (4 weeks old) and mature (15 weeks) rats. The plasma cholesterol level and its distribution among the major lipoprotein density fractions were similar in both groups. Using [3H]water as a substrate for measuring sterol synthesis in vivo, the content of newly synthesized cholesterol (3H-labeled digitonin-precipitable sterols; [3H]DPS) was several fold higher in all tissues of the young, compared to the old, rats when normalized per g of tissue. In contrast, whole-body [3H]DPS content was identical at 29.5 and 29.3 mumol/hr in young and old rats, respectively, despite a 4.4-fold difference in body weight (102 vs. 453 g). The importance of different organs to total-body sterol synthesis remained similar with increasing age although the skin (11 vs. 24% of total) rather than the small bowel (15 vs. 8%) became the second most important organ after the liver (49 vs. 45%) in the older animals. When LDL uptake was determined in these same organs, using constant infusion technique, the rates of clearance were higher only in the adrenal glands, adipose tissue, and skin of the young animals; whereas these rates were essentially the same in the liver and gastrointestinal tract, the two organs that are quantitatively most important for LDL catabolism. Even when these clearance rates were normalized to the whole organ or to 100 g of body weight, the differences in LDL uptake in the two age groups were minor compared to the major decrease in rates of cholesterol synthesis that were observed with aging. Finally, calculation of absolute rates of tissue cholesterol acquisition from both sources indicated that, in most organs, the majority of tissue cholesterol was derived from local synthesis rather than from LDL uptake in both age groups and that, with increasing age, total cholesterol acquisition decreased several-fold primarily as a consequence of the diminished rate of sterol synthesis. These studies demonstrate that with growth and aging in the rat there is a dramatic decrease in the rate of tissue cholesterol synthesis while the uptake of LDL-cholesterol remains essentially unchanged.

Aging↗

PubMed1984

Modulation of the stimulatory effect of pregnenolone-16 alpha-carbonitrile on biliary cholesterol output in the rat by manipulation of the rate of hepatic cholesterol synthesis.

In female rats fed a plain ground diet containing pregnenolone-16 alpha-carbonitrile, biliary cholesterol output increased twofold, whereas bile acid and phospholipid output either remained unchanged or decreased slightly. There was a 32% increase in liver weight, a 3.5-fold increase in cholesteryl esters, and a 45% decrease in the rate of hepatic sterol synthesis. When pregnenolone-16 alpha-carbonitrile was fed with AOMA, an agent that blocks cholesterol absorption, there was less of an increase in cholesteryl esters, the inhibitory effect of pregnenolone-16 alpha-carbonitrile on hepatic sterol synthesis was abolished, and biliary cholesterol output was increased to an even greater extent. In contrast, when pregnenolone-16 alpha-carbonitrile was fed together with cholesterol, there was a 14-fold increase in the level of cholesteryl esters, an 85% decrease in the rate of hepatic sterol synthesis, and a marked reduction in biliary cholesterol output. The increase in biliary cholesterol saturation produced by either pregnenolone-16 alpha-carbonitrile alone or pregnenolone-16 alpha-carbonitrile with AOMA occurred with little or no change in plasma cholesterol levels and bile acid pool size. Because biliary cholesterol saturation in rats given pregnenolone-16 alpha-carbonitrile appears to correlate with the rate of hepatic cholesterol synthesis, the drug likely mediates its effect on biliary lipid composition at an intrahepatic level and may provide an important model for determining how overproduction of cholesterol by the body results in excessive transport of cholesterol into bile.

Animals↗