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Lipid and Lipoprotein Research Group and Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada
2To whom correspondence should be addressed. LBA is a Senior Scholar of the Alberta Heritage Foundation for Medical Research.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • acyl CoA cholesterol acyl transferase • bile composition • cholesterol 7
-hydroxylase • 3-hydroxy-3-methylglutaryl coenzyme A reductase • mice • stearic acid
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,
Grundy and Denke 1990
, Hegsted et al. 1965
, Keys et al. 1965
). In general, the levels
of plasma cholesterol and the net cholesterol balance in the whole body
depend upon the events taking place in the liver.
The liver plays an important role in maintaining whole-body
cholesterol homeostasis by controlling uptake of extracellular
cholesterol, cholesterol synthesis and storage of cholesterol
(Dietschy et al. 1993a
). The excess levels of
cholesterol in the liver are converted to metabolically inert
cholesterol esters (CE)3
for storage. This process is
catalyzed by acyl coenzyme A:cholesterol acyltransferase (ACAT; EC
2.3.1.26) and is influenced by the type of fatty acid (Johnson et al. 1983
, Mitropoulos et al. 1980
,
Rumsey et al. 1995
, Spector et al. 1980
).
Situations that lead to a net increase in the flux of cholesterol into
liver generally stimulate ACAT activity and raise hepatic CE content.
On the other hand, an increase in the intrahepatic cholesterol content
typically inhibits the 3-hydroxy-3-methylglutaryl coenzyme A reductase
(HMGR; EC 1.1.1.34) activity, thereby inhibiting de novo cholesterol
biosynthesis (Dietschy et al. 1993a
, Hwa et al. 1992
). Dietary fats have also been shown to influence
hepatic HMGR activity (Field et al. 1987
, Hwa et al. 1992
, Mitropoulos et al. 1980
).
Liver is the major site of cholesterol removal by direct secretion to
bile or after breakdown to bile acids. The enzyme cholesterol
7-hydroxylase (cyp7; EC 1.14.13.17) is the first and the
rate-limiting enzyme in the conversion of cholesterol to bile acids
(Russell and Setchell 1992
). Cholesterol is generally
thought to stimulate cyp7 gene expression; however, recent studies do
not always agree with this contention (Krause et al. 1994
, Rudel et al. 1994
, Xu et al. 1995
). Previous studies from our laboratory indicated that the
response of the cyp7 gene to dietary cholesterol is dependent on the
type of dietary fat (Cheema et al. 1997
). A diet rich in
polyunsaturated fatty acids (PUFA) allows the stimulation of cyp7 gene
expression by dietary cholesterol, whereas in diets rich in
monounsaturated or saturated fatty acids, dietary cholesterol inhibits
the cyp7 gene expression.
Saturated fatty acids generally increase plasma cholesterol
concentration, whereas polyunsaturated fats have a plasma
cholesterol–lowering effect (Hegsted et al. 1965
,
Keys et al. 1965
). Interestingly, stearic acid was not
found to be hypercholesterolemic compared with other lower-chain
saturated fatty acids. This observation is supported by more recent
studies (Hassel et al. 1997
, Imaizumi et al. 1993
, Monsma et al. 1996
, Salter et al. 1998
). The basis for this effect is unclear, but poor
digestibility and absorption of dietary fats rich in 18:0 as well as
increased fecal excretion of sterols have been proposed as possible
mechanisms (Bergstedt et al. 1991
, Feldman et al. 1983
, Imaizumi et al. 1993
, Monsma et al. 1996
, Salter et al. 1998
). This investigation
was undertaken to determine the effect of the different fat diets on
the hepatic metabolism of cholesterol.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Female mice (C3H, 8 wk old) obtained from Jackson Laboratory (Bar
Harbor, ME) were housed in a room with a reverse light cycle (lights on
from 1700 to 0500 h) and fed a nonpurified diet (Rodent Laboratory
Chow 5001, Ralston Purina, St. Louis, MO) beginning 1 wk before the
initiation of the controlled diet study. All experimental protocols
were approved by the University of Alberta Health Sciences Animal
Welfare Committee. Mice (n = 6/group, 6 groups)
were fed for 3 wk a semipurified diet (Teklad #84172, Harlan Teklad,
Madison, WI) containing 20 g/100 g fat from either beef tallow
(saturated fatty acids; SFA), olive oil (monounsaturated fatty acids,
MUFA) or safflower oil (polyunsaturated fatty acids, PUFA), in the
absence or presence of cholesterol (1 g/100 g) (Cheema et al. 1997
). The composition of the diets is given in Table 1
. Mice were given free access to food and water. The gain in body weight
and food intake were recorded twice per week. The mice fed high fat
diets with or without cholesterol showed no significant differences in
food consumption or body weight gain throughout the study.
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Mice were killed 3 h after the onset of the last dark photoperiod (13–15 h after withdrawal of food). Blood was collected via cardiac puncture in a syringe containing 1 g EDTA/L. Plasma was separated and assayed for total cholesterol using enzymatic methods (kit #352, Sigma-Aldrich diagnostic, St. Louis, MO).
The plasma cholesterol profile was determined from pooled plasma
samples (equal volumes from each mouse) from each diet group. The
plasma samples were separated by HPLC on a Pharmacia Superose 6 column
(Baie d'Urté, PQ) attached to a Beckman System Gold apparatus
(Mississauga, ON) as described (Kieft et al. 1991
).
Cholesterol was detected using an on-line enzymatic assay by mixing
the column effluent with a cholesterol assay reagent (kit #352,
Sigma-Aldrich) and incubation in a post-column reactor. The
absorbance of the post-column effluent reflects the relative
concentration of cholesterol. Peaks corresponding to lipoproteins were
identified by comparison with lipoprotein standards.
Gallbladder bile was collected by aspiration, and cholesterol, bile
acid and phospholipid concentrations were measured as described earlier
(Cheema et al. 1997
). The cholesterol saturation index
(CSI) was calculated according to the method of Carey (1978)
. Liver pieces (50 mg) were taken for lipid extraction
using chloroform/methanol (2:1) (Yokode et al. 1990
),
and the amounts of total and free cholesterol were determined by
enzymatic methods (kit #352 for total cholesterol, Sigma-Aldrich
and kit #139050 for free cholesterol, Boehringer Mannheim, Laval,
Canada).
Assay for cyp7, HMGR and ACAT activities.
Microsomes were prepared from liver homogenates as described previously
(Cheema et al. 1997
). Microsomal cyp7 activity
[pmol/(min·mg protein)] was measured by following the conversion of
[14C]-cholesterol to 7-hydroxycholesterol as described
previously (Agellon 1997
). The HMGR activity
[nmol/(min·mg protein)] was assayed in the microsomes by
determining the conversion of [14C]HMG-CoA to mevalonate
(Shapiro et al. 1974
). For assay of ACAT activity in
purified microsomes, the incorporation of [14C]oleoyl
coenzyme A into cholesteryl esters [pmol/(min·mg protein)] was
determined using 100 µg of microsomal protein and 23
µg of exogenous cholesterol (Oram 1986
). In these assays, the radioactivity in the spots
corresponding to the specific reaction products generated by each
reaction was quantitated using a phosphorimager after separation by
TLC. Radiolabeled substrates and reference standards were obtained from
Amersham Life Science (Oakville, Canada) and Steraloids (Wilton, NH).
Microsomal and biliary fatty acid analysis.
Lipids were extracted from liver microsomal preparations and
gallbladder bile using chloroform/methanol (2:1). Phosphatidylcholine
(PC) was isolated from bile lipids. Fatty acid methyl esters were
prepared from microsomal lipids and biliary PC and then analyzed by
automated gas-liquid chromatography as described previously
(Cheema et al. 1997
).
Statistical analysis.
The effects of dietary manipulations on cholesterol, bile acids, phospholipids and enzyme activities were compared using two-way ANOVA (SAS/GLM Version 5.18, SAS Institute, Cary, NC). Differences among means were inspected using Duncan's multiple range test and were considered to be significant at P < 0.05. Values are reported as means ± SD
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mice fed the SFA diet enriched in 18:0 had lower plasma total
cholesterol levels in the absence and presence of cholesterol
(Table 2
) than mice fed diets containing fats enriched in MUFA or PUFA
(P < 0.05). The majority of plasma cholesterol was
associated with the HDL fraction as analyzed by HPLC (Fig. 1
). HDL was the predominant carrier of cholesterol in mice fed diets
enriched with specific fats, regardless of cholesterol supplementation.
Addition of cholesterol to the fat diets led to an apparent
redistribution of cholesterol in the lipoprotein fractions. The
increase in VLDL-associated cholesterol was most evident for mice
fed cholesterol in the MUFA diet compared with mice fed cholesterol in
the PUFA or SFA diet (Fig. 1)
. The LDL cholesterol fraction revealed
only minor differences due to dietary cholesterol, although larger
particles were apparent in mice fed fat diets containing cholesterol.
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Mice fed the different fat diets without cholesterol did not differ in
hepatic total cholesterol concentration (Table 3
). Hepatic total cholesterol concentration was greater when cholesterol
was added to the fat diets in mice fed the PUFA and MUFA diets
(P < 0.05). Hepatic CE concentration was greater in
all diet groups when cholesterol was added to the fat diets
(P < 0.05). The magnitude of the difference was
greatest in mice fed the MUFA diet. Hepatic free cholesterol did not
differ among the groups. The microsomal free cholesterol concentration
was not affected by the type of dietary fat but it was higher
(P < 0.05) when cholesterol was added to the fat diets
(Table 3)
.
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In the mice fed the MUFA and PUFA diets, the major fatty acids in
microsomal membranes were similar to those represented in the diet
(Table 4
). There was less correspondence between dietary fatty acids and
microsomal fatty acid profile in the SFA-fed mice. Nevertheless,
the proportion of 18:0 in the microsomes from the SFA-fed mice was
higher than that in microsomes from the PUFA- and MUFA-fed mice.
The addition of cholesterol to the MUFA and SFA diets decreased the
levels of 18:0 with a corresponding increase in the levels of 18:1.
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In the absence of dietary cholesterol, biliary cholesterol and
phospholipid concentrations were higher in mice fed the SFA diet
(Table 5
) than in those fed the PUFA and MUFA diets (P < 0.05).
The bile acid concentrations did not differ among groups. The CSI was
variably affected by the fat diets (Table 5)
. As reflected by the CSI,
the bile of SFA-fed mice was not saturated with cholesterol despite
its high concentration. When cholesterol was added to the diets,
cholesterol concentration in bile of mice fed the MUFA and PUFA diets
was 77% (P < 0.05) and 37% (P < 0.05) greater, respectively, than that in mice fed the fat diets alone,
whereas no significant difference was observed in SFA-fed mice.
Dietary cholesterol also increased biliary phospholipid concentration
to 83 and 22% in mice fed the MUFA and PUFA diets, respectively,
compared with mice fed the fat diets alone. In contrast, dietary
cholesterol caused a 26% decrease in biliary phospholipid
concentration in SFA-fed mice. A 16% reduction in biliary bile
acid concentration was observed when cholesterol was added to the MUFA
diet. Addition of cholesterol to the MUFA and PUFA diets significantly
increased (P < 0.05) the CSI in bile, resulting in
cholesterol-saturated bile in the MUFA-fed mice. The CSI was
not affected by dietary cholesterol in mice fed the SFA diet. Analysis
of the biliary PC fatty acid composition in mice fed diets without
cholesterol did not reveal any apparent differences among the groups
(Table 6
), indicating that biliary PC acyl chain specificity is more resistant
to modification than PC in cellular membranes (Table 4)
.
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The HMGR activity was lower in MUFA-fed mice than PUFA- and
SFA-fed mice (P < 0.05) in the absence or presence
of dietary cholesterol (Fig. 2A
). Mice fed the fat diets containing cholesterol had significantly lower
HMGR enzyme activity (P < 0.05) than mice fed the fat
diets without cholesterol. The least inhibitory effect on HMGR enzyme
activity was evident in the cholesterol-supplemented SFA diet (27%
inhibition for SFA vs. 56% for PUFA and 60% for MUFA).
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B). Varying effects were observed when
cholesterol was added to the fat diets. Addition of cholesterol to the
PUFA diet increased the cyp7 activity relative to mice fed the PUFA
diet alone (P < 0.05). However, addition of
cholesterol to the MUFA and SFA diets inhibited the cyp7 activity
compared with mice fed these fat diets alone (P < 0.05).
Mice fed the SFA diet enriched in 18:0 had lower ACAT activity (Fig. 2
C) than mice fed the PUFA and MUFA diets (P
< 0.05). Addition of cholesterol to the fat diets increased the
ACAT activity (P < 0.05), and the greatest increase
was evident in mice fed the MUFA diet (92 vs. 64% for PUFA and 73%
for SFA).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Keys et al. 1965
). However, diets containing fats rich in 18:0, a
saturated fatty acid, have either a hypocholesterolemic effect or are
neutral (Hassel et al. 1997
, Keys et al. 1965
, Kritchevsky et al. 1982
, Monsma et al. 1996
, Salter et al. 1998
). The basis for
this observation is not well understood. In this study, we investigated
the effect of diets enriched in C-18 fatty acids that varied in degree
of saturation on the hepatic metabolism of cholesterol in mice.
The plasma cholesterol levels were lowest in mice fed the SFA (18:0)
diet compared with the PUFA (18:2) and MUFA (18:1) diets even in the
presence of cholesterol. The hepatic total and microsomal free
cholesterol concentrations were not different among mice fed the
dietary fats alone. Addition of cholesterol to the fat diets increased
the hepatic microsomal free cholesterol concentrations in all groups.
Interestingly, dietary cholesterol did not significantly raise the
hepatic total cholesterol concentration in SFA-fed mice. Thus, the
stearic acid–rich diet prevented the rise of hepatic cholesterol
concentration in response to dietary cholesterol in mice, similar to
observations in other species (Hassel et al. 1997
,
Imaizumi et al. 1993
, Monsma et al. 1996
,
Salter et al. 1998
).
The enzyme ACAT converts excess free cholesterol into CE. Although it
is generally believed that free cholesterol drives the activity of this
membrane-bound enzyme, fatty acids have been shown to alter ACAT
activity (Johnson et al. 1983
, Rumsey et al. 1995
, Spector et al. 1980
). In mice, the
18:1-fed groups consistently had the highest ACAT activity. Previously,
18:1 was shown to be incorporated efficiently into CE in vitro
(Goodman et al. 1964
). It was also demonstrated that
18:1 constitutes the majority of fatty acids in the CE fraction of
hamster liver irrespective of dietary fatty acid composition
(Daumerie et al. 1992
). On the other hand, a more recent
study found that the liver isoform of mouse ACAT produced in insect
cells utilized a variety of fatty acid substrates in vitro in a
comparable manner (Cases et al. 1998
). It remains to be
determined whether the substrate preference of mouse hepatic ACAT is
influenced by other factors in vivo. However, it is interesting to note
that the amount of cholesterol associated with the VLDL fraction after
cholesterol feeding was highest in mice fed the MUFA diet compared with
those fed the SFA or PUFA diets. In monkeys, VLDL secretion from the
liver is correlated directly with the hepatic CE content (Carr et al. 1995
). The same phenomenon may also be true in mice.
The hepatic ACAT activity was lower in SFA-fed mice compared with
the MUFA-fed mice despite sufficient concentrations of cholesterol
and 18:1 in the liver microsomes. The dietary fats uniquely altered the
microsomal fatty acid composition, and cholesterol supplementation
caused additional variation in microsomal fatty acid profiles, likely
as a result of the modification of desaturase enzyme activities
(Garg et al. 1986
, Landau et al. 1997
).
Nevertheless, the altered microsomal fatty acid composition may have an
influence on the accessibility of ACAT to its substrates.
The different fat diets had variable effects on the HMGR and the cyp7
activities, suggesting that the type of fatty acid influences the
amount of cholesterol in the putative regulatory pool, in addition to
influencing the accessibility of cholesterol in the substrate pool. It
is possible that membrane rigidity may also have a direct effect on the
enzymes themselves. The addition of exogenous cholesterol to all the
fat diets decreased the HMGR activity. The extent of reduction for the
HMGR activity was the least for the SFA-fed mice, and this was
consistent with the rather small increase in the hepatic total
cholesterol content. The HMGR activity was the lowest in the
MUFA-fed mice, whereas the plasma cholesterol levels were the
lowest in the SFA-fed mice, indicating that the hypocholesterolemic
effect of the SFA diet with or without cholesterol is not solely
attributable to a reduced rate of cholesterol biosynthesis in the
liver. On the other hand, the cyp7 activity was differentially
regulated by cholesterol when fed along with dietary fats rich in
different fatty acids as previously observed in C57BL/6 mice
(Cheema et al. 1997
). Because the cyp7 activity was
inhibited by dietary cholesterol in mice fed the MUFA and SFA diets,
the breakdown of cholesterol to bile acids does not have a major effect
on plasma cholesterol levels under these dietary conditions.
Increased fecal neutral sterol secretion has been observed in hamsters
fed diets enriched in 18:0 (Imaizumi et al. 1993
,
Salter et al. 1998
). In rats, it has been shown that
fats enriched in 18:0 are less efficiently absorbed than fats enriched
in 18:1 and 18:2 (Bergstedt et al. 1991
, Feldman et al. 1983
). Moreover, the efficiency of cholesterol
absorption by rats was also lower from diets containing 18:0 fats
(Feldman et al. 1983
). Thus, absorption of fat and
cholesterol might be reduced in SFA-fed mice relative to MUFA- and
PUFA-fed mice. Nevertheless, sufficient amounts of fat are absorbed
to cause the remodeling of hepatic microsomal membranes, and the
differences in HMGR, ACAT and cyp7 activities in mice fed fat diets
with cholesterol indicate that the liver is exposed to a greater
cholesterol flux. However, cholesterol does not accumulate in the
plasma or liver of SFA-fed mice to the same extent as in PUFA- or
MUFA-fed mice. Dietary cholesterol increased biliary cholesterol
concentration in both PUFA- and MUFA-fed mice but not in the
SFA-fed mice. The effects of C-18 fatty acids with varying degrees
of saturation on bile lipid secretion has not been well studied. It is
conceivable that 18:0 may promote secretion of cholesterol into bile
along with other biliary lipids and, subsequently, excretion from the
body.
Different inbred strains of mice differ in their sensitivities to
dietary cholesterol (Kirk et al. 1995
). Bile acids are
typically added to diets in most studies in which high amounts of fat
and cholesterol are fed to mice. However, bile acids have a large
effect on hepatic cholesterol metabolism (Jelinek et al. 1990
, Pandak et al. 1994
, Spady and Cuthbert 1992
). It would be interesting to compare the response
of the different strains of mice to dietary fat and cholesterol in the
absence of exogenous bile acids. In our studies, we have avoided
feeding bile acids along with fat and cholesterol. The plasma
cholesterol levels of C57BL/6 mice fed C-18 fats were similar
regardless of the degree of saturation. Feeding cholesterol with a diet
enriched with SFA to both C57BL/6 and C3H mouse strains consistently
caused the least increment in plasma and hepatic total cholesterol, and
did not increase the concentration of cholesterol in bile. Examination
of the metabolism of cholesterol in the liver of C3H mice indicates
that the saturation of C-18 fatty acids in the diets influences the
disposition of hepatic cholesterol.
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FOOTNOTES |
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3 Abbreviations used: ACAT, acyl coenzyme
A:cholesterol acyl transferase; CE, cholesterol esters; CSI,
cholesterol saturation index; cyp7, cholesterol 7-hydroxylase; HMGR,
3-hydroxy-3-methylglutaryl coenzyme A reductase; MUFA, monounsaturated
fatty acids; PC, phosphatidylcholine; PUFA, polyunsaturated fatty
acids; SFA, saturated fatty acids.
Manuscript received September 5, 1998. Initial review completed November 3, 1998. Revision accepted May 26, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1.
Agellon L. B. Partial transfection of liver with a synthetic cholesterol 7-hydroxylase transgene is sufficient to stimulate the reduction of cholesterol in the plasma of hypercholesterolemic mice. Biochem. Cell Biol. 1997;75:255-262[Medline]
2.
Bergstedt S. E., Bergstedt J. L., Fujimoto K., Mansbach C., Kritchevsky D., Tso P. Effects of glycerol tripalmitate and glycerol trioleate on intestinal absorption of glycerol tristearate. Am. J. Physiol. 1991;261:G239-G247
3. Carey M. C. Critical tables for calculating the cholesterol saturation of native bile. J. Lipid Res. 1978;19:945-955[Abstract]
4. Carr T. P., Hamilton R. L., Jr, Rudel L. L. ACAT inhibitors decrease secretion of cholesteryl esters and apolipoprotein B by perfused livers of African green monkeys. J. Lipid Res. 1995;36:25-36[Abstract]
5.
Cases S., Novak S., Zheng Y., Myers H. M., Lear S. R., Sande E., Welch C. B., Lusis A. J., Spencer T. A., Krause B. R., Erickson S. K., Farese R. V. ACAT-2, a second mammalian acyl-CoA:cholesterol acyltransferase, its cloning, expression and characterization. J. Biol. Chem. 1998;273:26755-26764
6.
Cheema S. K., Cikaluk D., Agellon L. B. Dietary fats modulate the regulatory potential of dietary cholesterol on cholesterol 7-hydroxylase gene expression. J. Lipid Res. 1997;38:315-322[Abstract]
7.
Daumerie J. M., Woollett L. A., Dietschy J. M. Fatty acids regulate hepatic low density lipoprotein receptor activity through redistribution of intracellular cholesterol pools. Proc. Natl. Acad. Sci. U.S.A. 1992;89:10797-10801
8. Dietschy J. M., Turley S. D., Spady D. K. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J. Lipid Res. 1993;34:1637-1659[Medline]
9. Dietschy J. M., Woollett L. A., Spady D. K. The interaction of dietary cholesterol and specific fatty acids in the regulation of LDL receptor activity and plasma LDL-cholesterol concentrations. Ann. N.Y. Acad. Sci. 1993;676:11-26[Abstract]
10. Feldman E. B., Russell B. S., Hawkins C. B., Forte T. Intestinal lymph lipoproteins in rats fed diets enriched in specific fatty acids. J. Nutr. 1983;113:2323-2334
11. Field F. J., Albright E. J., Mathur S. N. Effect of dietary n-3 fatty acids on HMG-CoA reductase and ACAT activities in liver and intestine of the rabbit. J. Lipid Res. 1987;28:50-58[Abstract]
12. Garg M. L., Snoswell A. M., Sabine J. R. Influence of dietary cholesterol on desaturase enzymes of rat liver microsomes. Prog. Lipid Res. 1986;25:639-644[Medline]
13.
Goodman D. S., Deykin D., Shiratori T. The formation of cholesterol esters with rat liver enzymes. J. Biol. Chem. 1964;239:1335-1345
14. Grundy S. M., Denke M. A. Dietary influences on serum lipids and lipoproteins. J. Lipid Res. 1990;31:1149-1172[Abstract]
15.
Hassel C. A., Mensing E., A & Gallaher D. D. Dietary stearic acid reduces plasma and hepatic cholesterol concentrations without increasing bile acid excretion in cholesterol-fed hamsters. J. Nutr. 1997;127:1148-1155
16. Hegsted D. M., McGandy R. B., Meyers M. L., Stare F. J. Quantitative effects of dietary fats on serum cholesterol in man. Am. J. Clin. Nutr. 1965;17:281-295[Medline]
17. Hwa J., Zollman S., Warden C. H., Taylor B. A., Edwards P. A., Fogelman A., Lusis A. J. Genetic and dietary interactions in the regulation of HMG CoA reductase gene expression. J. Lipid Res. 1992;33:711-725[Abstract]
18. Imaizumi K., Abe K., Kuroiwa C., Sugano M. Fat containing stearic acid increases fecal neutral steroid excretion and catabolism of low density lipoproteins without affecting plasma cholesterol concentration in hamsters fed a cholesterol-containing diet. J. Nutr. 1993;123:1693-1702
19.
Jelinek D. F., Andersson S., Slaughter C. A., Russell D. W. Cloning and characterization of cholesterol 7-hydroxylase, the rate limiting enzyme in bile acid biosynthesis. J. Biol. Chem. 1990;265:8190-8197
20.
Johnson M. R., Mathur S. N., Coffman C., Spector A. A. Dietary fat saturation and hepatic acylcoenzyme A:cholesterol acyltransferase activity. Effect of n-3 polyunsaturated and long chain saturated fat. Arteriosclerosis 1983;3:242-248
21. Keys A., Anderson J. T., Grande F. Serum cholesterol response to changes in the diet. IV. Particular saturated fatty acids in the diet. Metabolism 1965;14:776-787
22. Kieft K. A., Bocan T.M., A & Krause B. R. Rapid on-line determination of cholesterol distribution among plasma lipoproteins after high-performance gel filtration chromatography. J. Lipid Res. 1991;32:859-866[Abstract]
23. Kirk E. A., Moe G. L., Caldwell M. T., Lernmark J. A., Wilson D. L., LeBoeuf R. C. Hyper- and hypo-responsiveness to dietary fat and cholesterol among inbred mice: searching for level and variability genes. J. Lipid Res. 1995;36:1522-1532[Abstract]
24.
Krause B. R., Pape M. E., Kieft K., Auerbach B., Bisgaier C. L., Homan R., Newton R. S. ACAT inhibition decreases LDL cholesterol in rabbits fed a cholesterol-free diet. Arterioscler. Thromb. 1994;14:598-604
25. Kritchevsky D., Tepper S. A., Bises G., Klurfeld D. M. Experimental atherosclerosis in rabbits fed cholesterol-free diets. Part 10. Cocoa butter and palm oil. Atherosclerosis 1982;41:279-284[Medline]
26. Landau J. M., Sekowski A., Hamm M. W. Dietary cholesterol and the activity of stearoyl CoA desaturase in rats: evidence for an indirect regulatory effect. Biochim. Biophys. Acta 1997;1345:349-357[Medline]
27. Mitropoulos K. A., Venkatesan S., Subramaniam S. On the mechanism of regulation of 3-hydroxy 3-methyl glutaryl coenzyme A reductase and of acyl coenzyme A:cholesterol acyltransferase of dietary fat. Biochim. Biophys. Acta 1980;619:247-257[Medline]
28. Monsma C. C., Gallaher D. D., Ney D. M. Reduced digestibility of beef tallow and cocoa butter affects bile acid excretion and reduces hepatic esterified cholesterol in rats. J. Nutr. 1996;126:2028-2035
29. Oram J. F. Receptor-mediated transport of cholesterol between cultured cells and high-density lipoproteins. Methods Enzymol 1986;129:645-659[Medline]
30.
Pandak W. M., Vlahcevic Z. R., Heuman D. M., Redford K. S., Chiang J.Y., L & Hylemon P. B. Effects of different bile salts on the steady state mRNA levels and transcriptional activity of cholesterol 7- hydroxylase. Hepatology 1994;19:941-947[Medline]
31.
Rudel L., Deckelman C., Wilson M., Scobey M., Anderson R. Dietary cholesterol and downregulation of cholesterol 7-hydroxylase and cholesterol absorption in African green monkeys. J. Clin. Investig. 1994;93:2463-2472
32.
Rumsey S. C., Galeano N. F., Lipschitz B., Deckelbaum R. J. Oleate and other long chain fatty acids stimulate low density lipoprotein receptor activity by enhancing acyl coenzyme A:cholesterol acyltransferase activity and altering intracellular regulatory cholesterol pools in cultured cells. J. Biol. Chem. 1995;270:10008-10016
33. Russell D. W., Setchell K.D.R. Bile acid biosynthesis. Biochemistry 1992;31:4737-4749[Medline]
34. Salter A. M., Mangiapane E. H., Bennett A. J., Bruce J. S., Billett M. A., Anderton K. L., Marenah C. B., Lawson N., White D. A. The effect of different fatty acids on lipoprotein metabolism: concentration-dependent effects of diets enriched in oleic, myristic, palmitic and stearic acids. Br. J. Nutr. 1998;79:195-202[Medline]
35. Shapiro D. J., Nordstrom J. L., Mitschelen J. J., Rodwell V. W., Schmike R. T. Micro assay for 3-hydroxy-3-methyl-glutaryl-CoA reductase in rat liver and in L-cell fibroblasts. Biochim. Biophys. Acta 1974;370:369-377[Medline]
36.
Spady D. K., Cuthbert J. A. Regulation of hepatic sterol metabolism in the rat. Parallel regulation of activity and mRNA for 7 alpha-hydroxylase but not 3-hydroxy-3-methylglutaryl-coenzyme A reductase or low density lipoprotein receptor. J. Biol. Chem. 1992;267:5584-5591
37. Spector A. A., Kaduce T. L., Dane R. W. Effect of dietary fat saturation on acylcoenzyme A:cholesterol acyltransferase activity of liver microsomes. J. Lipid Res. 1980;21:169-179[Abstract]
38.
Xu G., Salen G., Shefer S., Ness G. C., Nguyen L. B., Parker T. S., Chen T. S., Zhao Z., Donnelly T. M., Tint G. S. Unexpected inhibition of cholesterol 7-hydroxylase by cholesterol in New Zealand white and Watanabe heritable hyperlipidemic rabbits. J. Clin. Investig. 1995;95:1497-1504
39.
Yokode M., Hammer R. E., Ishibashi S., Brown M. S., Goldstein J. L. Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors. Science (Washington, DC) 1990;250:1273-1275
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