Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-8887
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ABSTRACT |
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This study compared the cholesterolemic response of two strains of mice with genetically determined differences in cholesterol absorption. When fed a basal low-cholesterol diet, 129/Sv mice absorbed cholesterol twice as efficiently as did C57BL/6 mice (44% vs. 20%). Total lipid absorption, in contrast, averaged 80-82% in both strains. The higher level of cholesterol absorption in the 129/Sv animals was reflected in an adaptive reduction in hepatic and intestinal sterol synthesis. When fed lipid-enriched diets, the 129/Sv mice became significantly more hypercholesterolemic and had twofold higher hepatic cholesterol concentrations than did the C57BL/6 animals even though the conversion of cholesterol to bile acids was stimulated equally in both strains. The difference in cholesterol absorption between these mouse strains was not the result of physicochemical factors relating to the size and composition of the intestinal bile acid pool but more likely reflects an inherited difference in one or more of the biochemical steps that facilitate the translocation of sterol across the epithelial cell.
cholesterol esterification; hepatic sterol synthesis; small intestine; fecal sterol excretion; cholesterol transport
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INTRODUCTION |
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INCREASED LEVELS OF PLASMA low-density lipoprotein (LDL)-cholesterol (LDL-C) constitute a major risk for the development of atherosclerosis (22, 23). The cholesterol carried in LDL, like all cholesterol throughout the body, is derived ultimately from de novo synthesis and by absorption from the diet (38). In humans plasma LDL-C levels correlate positively with the level of intestinal cholesterol absorption (13, 21). This is also the case in various primate models that have been identified as being either hypo- or hyperresponsive to a dietary cholesterol challenge (2, 18, 33, 41).
The major biochemical steps involved in the translocation of cholesterol from the intestinal lumen to the lymph have been described in detail (36). It is also well documented that the level of cholesterol absorption can be dramatically changed by manipulating some, but not all, of these steps (9, 10). In particular, changes in the physicochemical environment within the intestinal lumen that result from either spontaneous or induced shifts in the size and composition of the bile acid pool, or in the phospholipid content of bile entering the lumen, bring about profound changes in cholesterol absorption (5, 28, 39, 42, 43). Similar effects result from the pharmacological manipulation of the activity of acyl-CoA:cholesterol acyltransferase (ACAT) (9).
Despite all of these findings, it is not clear which step(s) in the absorption process may differ inherently among individuals in any population in a way that explains their differences in dietary cholesterolemic response. This understanding is essential for the development of more efficacious compounds for reducing hypercholesterolemia in the general population through the inhibition of cholesterol absorption (9, 17). One of the challenges in fulfilling this objective is the availability of suitable animal models. Although there are several species of primates that would be ideal for such research, various factors relating mainly to expense and concerns about disease transmission usually exclude their use.
During the course of recent studies on bile acid and sterol metabolism in different strains of mice fed a low-cholesterol basal rodent diet (40), we found that the level of cholesterol absorption, as measured by a fecal isotope ratio method, was twice as high in 129/Sv mice as in C57BL/6 mice. Further investigation of this key metabolic difference was warranted because mice bearing the genetic makeup of these two strains have been used extensively for gene targeting experiments and because evaluation of the phenotype of animals generated by these experiments can be confounded by genetic strain differences (31, 32, 35). Therefore, the objective of the present studies was to fully characterize all aspects of cholesterol metabolism in these two strains, to test their response to challenge with cholesterol- and fat-enriched diets, and to explore possible mechanisms that might account for the propensity of the 129/Sv mice to absorb cholesterol so much more efficiently than their C57BL/6 counterparts.
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MATERIALS AND METHODS |
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Animals and diets. Unless otherwise stated, all the 129/Sv mice used in these studies were generated within our own colony, whereas the C57BL/6 mice were obtained from the Jackson Laboratory (Bar Harbor, ME). This was also the source of additional 129/Sv and 129 mice that were used in one experiment for direct comparison with our 129/Sv animals. Our colony of 129/Sv mice was derived from 129/SvEvBrd-Hprtb-m2 breeding stock provided by Bradley as described (31) and has remained closed since its establishment in 1994. All mice were housed either as groups or individually in plastic colony cages containing wood shavings. The animals were maintained in a room at 72-74°F with alternating 12-h periods of light (11 AM to 11 PM) and dark (11 PM to 11 AM). They had access to drinking water at all times and were fed ad libitum a pelleted cereal-based rodent diet (no. 8604; Harlan Teklad, Madison, WI). This formulation (basal diet) had an inherent cholesterol content of 0.02% (wt/wt) and a fatty acid composition as described elsewhere (39). The meal form of this diet was used to prepare various experimental diets that contained either cholic acid (0.01% wt/wt), chenodeoxycholic acid (0.01% wt/wt), cholesterol (1.0% wt/wt; Byron Chemical, Long Island City, NY), cholesterol (1.0% wt/wt) combined with hydrogenated coconut oil (10% wt/wt; ICN Pharmaceuticals, Costa Mesa, CA), or cholesterol (1.0% wt/wt) combined with olive oil (10% wt/wt; Bertolli USA, Secaucus, NJ). The diets with added bile acids were fed for 14 days, whereas those enriched with cholesterol and oil were fed for 21 days. In all experiments the mice were ~3 mo of age and were studied in the fed state, except in one case in which gallbladder bile was harvested from mice that had been fasted for 4 h. All experiments were approved by the Institutional Animal Care and Research Advisory Committee.
Measurement of intestinal cholesterol and lipid absorption. Cholesterol absorption was measured by a fecal dual-isotope ratio method using [4-14C]cholesterol (NEN, Boston, MA) and [5,6-3H]sitostanol (stigmastanol) (American Radiolabeled Chemicals, St. Louis, MO) as described (28). The stools were collected from each animal over a 72-h period immediately after dosing with the labeled sterols contained in medium-chain triacylglycerol (MCT) oil. The mice were dosed toward the end of the dark phase of the lighting cycle. Aliquots of ground stool and the dosing mixture were extracted, and the ratio of 14C to 3H in each was determined. The percent cholesterol absorption was calculated from these data as described (28). In one study the cholesterol absorption measurements were made on stools that were collected during only the first 24 h after dosing, and in another experiment the dosing mixture was prepared using corn oil in place of MCT oil. To determine the level of total lipid absorption, the lipid content of the diet and stools was determined gravimetrically. These data, together with the amount of diet consumed and stool excreted, were used to calculate the fraction of lipid consumed that was absorbed.
Measurement of fecal bile acid excretion and bile acid pool size and composition. Stools collected from individually housed mice over 72 h were dried, weighed, and ground. The rates of fecal bile acid excretion were measured as previously described (28) and expressed as micromoles per day per 100 g body weight. Bile acid pool size was determined using an HPLC method as the total bile acid content of the small intestine, gallbladder, and liver combined (28). Pool size was expressed as micromoles per 100 g body weight. The total bile acid concentration in gallbladder bile was measured enzymatically (28).
Measurement of sterol synthesis. The rate of hepatic and intestinal sterol synthesis was measured in vivo as described previously (28). The mice were given an intraperitoneal injection of ~40 mCi of 3H-labeled water (NEN) and after 1 h were anesthetized and exsanguinated. Aliquots of liver and the whole small intestine were digested, and their content of digitonin-precipitable sterols was measured. The rate of sterol synthesis in each organ was expressed as nanomoles of 3H-labeled water incorporated into sterol per hour per gram of tissue.
Measurement of plasma, hepatic, biliary, and dietary cholesterol. Plasma total cholesterol concentrations were determined enzymatically, whereas dietary and hepatic and biliary cholesterol levels were measured by gas-liquid chromatography as previously described (28, 39).
Analysis of data. The data are presented as means ± SE of measurements in the specified number of individual animals. Differences between these mean values were tested for statistical significance by the two-tailed Student's t-test.
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RESULTS |
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The data in Table 1 show that, when fed a
basal rodent diet without added cholesterol, the two strains of mice
exhibited very similar characteristics, except for plasma cholesterol
levels, which were marginally higher in the 129/Sv animals. In
gallbladder bile obtained from separate groups of mice that had been
fasted for 4 h, there was no strain difference in the absolute
concentrations of either cholesterol [3.8 ± 0.3 µmol/ml in
129/Sv (n = 8) vs. 3.3 ± 0.3 µmol/ml in C57BL/6
(n = 7)] or bile acid [180 ± 17 µmol/ml in 129/Sv
(n = 8) vs. 175 ± 12 µmol/ml in C57BL/6
(n = 7)].
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In both strains, the level of intestinal total lipid absorption
averaged 80-82% (Fig. 1A),
but the efficiency of cholesterol absorption in the 129/Sv mice
(44 ± 3%) was substantially greater than in matching C57BL/6
animals (20 ± 3%) (Fig. 1B). The comparatively high
level of cholesterol absorption found in 129/Sv mice from our own
colony was equally apparent in 129/Sv and 129 strains obtained directly
from Jackson Laboratory [41 ± 4% in 129/Sv mice (n = 9)
and 52 ± 4% in 129 mice (n = 10)]. When stools were
collected for only 24 h instead of 72 h after dosing, the strain
difference in cholesterol absorption was still evident [63 ± 9%
(n = 5) in 129/Sv mice vs. 39 ± 4% (n = 4) in
C57BL/6 mice], but the values were higher in each case than those
found from analysis of stools collected over 72 h. A similar result was
obtained when corn oil replaced MCT oil in the dosing mixture. The more
efficient absorption of cholesterol in 129/Sv mice was reflected in a
marked compensatory reduction in the rate of cholesterol synthesis in
both the liver and small intestine (Fig.
2).
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Although bile acid pool size was not different in these two types of
mouse (Fig. 3A), the proportion
of cholic to muricholic acid in the pool of the 129/Sv mice was ~30%
higher (P < 0.05) than in the C57BL/6 mice. In other animal
models, enrichment of the bile acid pool with cholic acid raises the
level of intestinal cholesterol absorption (28, 39). To determine
whether the higher proportion of cholic acid in the pool of the 129/Sv
animals accounted for their inherently higher levels of cholesterol
absorption compared with that manifest in the C57BL/6 animals, the pool
composition in each strain was manipulated so as to bring the ratio of
cholic to muricholic acid in the pool of each type of
mouse toward more similar values. This was achieved by adding
chenodeoxycholic acid (a precursor of muricholic acid) to the diet of
the 129/Sv mice and cholic acid to the diet of the C57BL/6 mice. Each
bile acid was incorporated into the diet at a level of only 0.01%
(wt/wt) so as to facilitate a subtle shift in pool composition without expanding pool size. Intestinal cholesterol absorption was measured in
the bile acid-fed animals, as well as in matching groups of mice of
both strains that were fed only the plain rodent diet. In these
unsupplemented groups, pool size was again the same in both strains
(Fig. 4A), and the proportion of
cholic acid relative to muricholic acid was significantly higher in the
129/Sv mice (Fig. 4B), as was the percent cholesterol
absorption (Fig. 4C). In the bile acid-supplemented groups
there was no change in respective pool sizes (Fig. 4A), but
the ratio of cholic to muricholic acid decreased in the pool of the
129/Sv animals and increased in the pool of the C57BL/6 animals (Fig.
4B). Although the difference in pool composition between the
two types of mouse was now markedly reduced in the bile acid-fed
animals, the strain difference in cholesterol absorption prevailed
(Fig. 4C).
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The next study was designed to determine whether the inherent
difference in cholesterol absorption between these two strains of mice
was reflected in the propensity with which they accumulated cholesterol
in their plasma and liver when challenged with a diet that was enriched
with cholesterol alone or cholesterol combined with either coconut or
olive oil. As shown in Fig. 5A,
plasma cholesterol levels were raised by all three diets in both
strains, but in every case a significantly greater level of
hypercholesterolemia was manifest in the 129/Sv mice compared with
matching C57BL/6 mice fed the same diet. Although the addition of
cholesterol alone to the diet resulted in about a twofold increase in
hepatic cholesterol levels in both types of mice, the inclusion of
either coconut or olive oil in the cholesterol-rich diet resulted in
substantially more cholesterol accumulation in the liver of the 129/Sv
mice than was the case in their C57BL/6 counterparts (Fig.
5B). This was particularly the case with the cholesterol and
olive oil diet, which raised hepatic cholesterol concentrations in the
129/Sv animals to levels that were double those in the C57BL/6 animals (28.9 ± 1.0 vs. 14.2 ± 0.7 mg/g, respectively). Although the
data are not shown, essentially all of the excess hepatic cholesterol that accumulated in both strains of mice was present as cholesteryl ester. In a final study, it was further demonstrated that this strain
difference in hepatic cholesterol accumulation was not the result of a
difference in the ability of each type of mouse to convert excess
cholesterol to bile acid. Thus, as shown in Fig.
6, the rate of fecal bile acid excretion
was stimulated by about the same extent in both strains of mice when
fed the diet with added cholesterol and olive oil.
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DISCUSSION |
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Over the past decade, both C57BL/6 and various sublines of 129 mice, as well as crosses of these two strains, have been used extensively for generating genetically manipulated models in which numerous proteins involved in regulating the transport and metabolism of cholesterol have been either deleted or overexpressed (6, 11, 16, 24, 26, 28, 30, 44). The finding that the level of cholesterol absorption is so different in these two strains may be of particular importance when such models are used for cholesterol balance studies. Clearly, data obtained from such studies may vary significantly depending on whether a genetically altered model is derived from a pure 129 or C57BL/6 background or from a cross of these two strains. Mixed-background mice are likely to show greater animal-to-animal variability, particularly for data relating to intestinal cholesterol absorption.
Several other points pertaining to the difference in absorption between these two widely used strains warrant emphasis. First, the lower level of cholesterol absorption in the C57BL/6 mice was manifest in animals that had essentially the same level of total lipid absorption as was found in the 129/Sv strain. Furthermore, when the animals were challenged with the cholesterol- and fat-enriched diets, there was no evidence of lipid malabsorption in either strain. Second, the propensity of male 129/Sv mice from our colony to absorb cholesterol more efficiently than C57BL/6 mice is shared with other sublines of the 129 strain from commercial sources (unpublished observations) and is just as apparent in female as it is in male mice of this strain (3). Third, although there is already extensive literature describing differences between numerous strains of mice in susceptibility to atherosclerosis and cholelithiasis (14, 20, 25), many of these studies used lipid-enriched, semisynthetic diets that were supplemented with high levels of cholic acid. In the present studies the metabolic differences between 129/Sv and C57BL/6 mice were seen in animals fed a natural, cereal-based rodent diet. These differences might well have been distorted or masked altogether if the animals had been fed a traditional cholic acid-enriched atherogenic diet. Fourth, the absolute value obtained for percent cholesterol absorption for any group of animals will vary with many factors, including the method by which the measurement is made, the type of oil used as a vehicle for the intragastric administration of labeled sterols, and, in the case of the fecal-isotope ratio technique, the period over which the stools are collected after dosing (37, 39). The levels of absorption reported by other investigators for these two strains, especially the C57BL/6 mice, are generally higher than those found in our studies (3, 15, 29). Although these differences mainly reflect differences in the technique used, other factors, like the gender of the animals, need to be considered when such comparisons are made (40). The difference in absorption in the two strains studied here prevailed irrespective of the type of oil used in the dosing mixture or the period of stool collection after dosing. The lower percent absorption values for both strains found when a 3-day collection period was applied likely resulted because a portion of the labeled cholesterol absorbed during the first 24 h was subsequently excreted on the second or third day after dosing. Be that as it may, it is clear that the difference in cholesterol absorption between these two strains was not an artifact of the conditions of the fecal-isotope ratio method that is routinely utilized in this laboratory.
The data derived from the sterol synthesis and cholesterol feeding
experiments provided further evidence attesting to a difference in
cholesterol absorption between these two strains of mice. It is well
documented that the rate of hepatic cholesterol synthesis varies
inversely with the amount of chylomicron cholesterol reaching the liver
from the small intestine (38). The rate of sterol synthesis in the
intestinal mucosa is also often reflective of the level of cholesterol
absorption (28). In the present studies, the higher-absorbing 129/Sv
mice manifested markedly lower rates of hepatic and intestinal
cholesterol synthesis than their C57BL/6 counterparts. When the strains
were challenged with diets enriched with cholesterol and oil, the
difference between the two strains in the magnitude of the increase in
their plasma and hepatic cholesterol concentrations was fully
consistent with the difference that was manifest in their efficiency of
cholesterol absorption. Thus, irrespective of whether predominantly
saturated or unsaturated fat was added to the cholesterol-enriched
diet, the concentration of cholesterol in the liver was increased twice
as much in the high-absorbing 129/Sv mice as it was in the C57BL/6
mice. This difference was particularly striking in the groups fed the
diet with cholesterol and olive oil, which raised hepatic cholesterol levels to 14 mg/g in the C57BL/6 mice but to 29 mg/g in the 129/Sv strain. Three points regarding this exceptional response of the 129/Sv
mice are noteworthy. First, mice are generally resistant to dietary
cholesterol. In most strains, the feeding of high-cholesterol diets
usually results in only very modest increases in hepatic cholesterol
content (40), unless the mice either lack the LXR receptor or are
given a cholesterol-enriched diet that also contains high levels of fat
and cholic acid (25, 26). Second, although the data are not shown,
almost all of the excess cholesterol that accumulated in the livers of
both types of mice was esterified. Third, in both strains bile acid
synthesis was induced to the same extent in the groups fed the diet
with cholesterol and olive oil. Hence, the strain difference in hepatic
cholesterol accumulation in the groups given this diet could not be
attributed to a difference in the ability of each type of mouse to
upregulate the conversion of excess cholesterol to bile acids.
The question thus arises as to which step(s) in the absorption of cholesterol might be inherently different, not just in the two strains of mice studied here, but in other strains as well. Within the intestinal lumen there are a number of processes involved in the handling of cholesterol from endogenous and exogenous sources that are essential for its subsequent movement into the epithelial cell (36). One of these involves the action of pancreatic cholesterol esterase. Controversy surrounding the importance of this lipolytic enzyme as a regulator of cholesterol absorption was recently settled with the finding that deletion of the gene for this protein in mice did not significantly change the efficiency with which cholesterol was absorbed (10). Thus the difference in absorption between various strains of mice is probably not due to differences in the expression of this particular enzyme.
The other major intraluminal process that is involved in preparing
cholesterol for its absorption is its micellerization by bile acids and
phospholipids (36). The importance of phospholipids in this process has
recently been clearly demonstrated in mice lacking the gene for the
Mdr2 P-glycoprotein. In these animals, the biliary secretion rates of
phospholipid and of cholesterol, but not of bile acid, fall
dramatically, and there is a marked reduction in the efficiency of
cholesterol absorption (42, 43). Although biliary phospholipid
secretion was not measured in the mice studied here, the ratio of the
concentrations of cholesterol to bile acid in gallbladder bile was the
same in both strains. This can be taken as an indication that the
difference in cholesterol absorption between these two strains was, at
least, not the result of a difference in the extent to which the
labeled cholesterol contained in the dosing mixture was diluted by
biliary cholesterol. The strain difference in absorption also could not
be attributed to differences in the size or composition of the
intestinal bile acid pool. Although pool size was identical in both
strains, the partially greater enrichment of the pool with cholic acid
in the 129/Sv mice was initially considered a possible cause of the
higher levels of absorption in this strain. This followed from numerous earlier studies, including those recently described in the cholesterol 7-hydroxylase-knockout mouse (28). In that model, bile acid pool
size is dramatically reduced and the animals do not absorb cholesterol.
This condition is readily reversed by feeding a diet containing 0.2%
(wt/wt) cholic acid. In the present study a dietary cholic acid level
of only 0.01% (wt/wt) was needed to raise the proportion of this bile
acid in the pool of the C57BL/6 mice closer to that which occurred
spontaneously in their 129/Sv counterparts. Conversely, feeding the
same dietary level of chenodeoxycholic acid to the 129/Sv animals
lowered the proportion of cholic acid in their pool more toward the
level characteristic of the C57BL/6 animals. Importantly, these subtle
shifts in pool composition were achieved without expanding pool size in
either strain. The finding that the level of cholesterol absorption was
still as different in the bile acid supplemented groups as it was in
matching unsupplemented animals showed unequivocally that the modest
difference in hydrophobicity of the bile acid pool between these two
strains of mice was not the cause of their inherently different levels of cholesterol absorption. These findings, however, do not preclude the
possibility that the level of absorption in the C57BL/6 mice could be
raised to at least that which is characteristic of 129/Sv mice by
feeding much higher doses of cholic acid.
Thus physicochemical effects within the intestinal lumen clearly play a decisive role in determining the quantity of cholesterol that moves from the lumen into the epithelial cells. However, although genetically determined differences in bile acid pool size and composition and biliary lipid secretion could potentially account for some inter- and intraspecies differences in cholesterol absorption, in the case of the two strains of mice studied here such genetic influences appear to be exerted on another step in the absorption process, and this step presumably involves the uptake and processing of cholesterol by the jejunal absorptive cell. There are multiple proteins that are involved in the transcellular movement and processing of cholesterol that potentially could be genetically regulated. These include caveolin, the scavenger receptor SR-BI, and the sterol carrier protein SCP-2, which facilitate the movement of unesterified cholesterol across cell membranes and through the cytosol, and the enzyme ACAT, which esterifies cholesterol before its incorporation into nascent chylomicron particles (7, 12, 27, 34, 36). Recent studies carried out in vitro showed that SR-BI functions in facilitating the movement of cholesterol and other lipids across the brush-border membrane (8). It is also now known that there are at least two forms of ACAT, one of which, ACAT-2, is located principally in the small intestine (1, 4, 19). Measurement of the expression and activity of these various types of proteins in C57BL/6 and 129/Sv mice will potentially yield new insights into the mechanism(s) responsible for the marked difference in cholesterol absorption between these two strains.
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ACKNOWLEDGEMENTS |
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We thank Jeffrey Graven, Brian Jefferson, Elizabeth Moore, Stephen Ostermann, and Monti Schneiderman for excellent technical assistance and Merikay Presley for expert preparation of the manuscript.
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FOOTNOTES |
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These studies were supported by National Heart, Lung, and Blood Institute Grant HL-09610 and National Institute of Diabetes and Digestive and Kidney Diseases Training Grant DK-07745, and by a grant from the Moss Heart Fund.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. D. Turley, Dept. of Internal Medicine, The Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-8887.
Received 10 December 1998; accepted in final form 9 February 1999.
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