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• W2142267239 abstract "These experiments tested the hypothesis that fatty acids (FAs) that drive cholesterol esterification also enhance sterol secretion and were undertaken using a mouse model where lipoprotein-cholesterol output by the liver could be assessed in vivo. The turnover of sterol in the animals was kept constant (∼160 mg/d per kg) while the liver was enriched with the single FAs 8:0, 14:0, 18:1, or 18:2. Under these conditions, the steady-state concentration of cholesteryl ester in the liver varied 6-fold, from 1.2 to 7.9 mg/g, and the expansion of this pool was directly related to the specific FA enriching the liver (FA 18:1>18:2>8:0> 14:0). Secretion of lipoprotein-cholesterol varied 5-fold and was a linear function of the concentration of cholesteryl ester in the liver. These studies demonstrate that unsaturated FAs drive the esterification reaction and enhance lipoprotein cholesterol secretion by the liver under conditions where cholesterol balance across this organ is constant.Thus, individual FAs interact with cholesterol to profoundly regulate both the output and uptake of sterol by the liver, and these effects are articulated through the esterification reaction. These experiments tested the hypothesis that fatty acids (FAs) that drive cholesterol esterification also enhance sterol secretion and were undertaken using a mouse model where lipoprotein-cholesterol output by the liver could be assessed in vivo. The turnover of sterol in the animals was kept constant (∼160 mg/d per kg) while the liver was enriched with the single FAs 8:0, 14:0, 18:1, or 18:2. Under these conditions, the steady-state concentration of cholesteryl ester in the liver varied 6-fold, from 1.2 to 7.9 mg/g, and the expansion of this pool was directly related to the specific FA enriching the liver (FA 18:1>18:2>8:0> 14:0). Secretion of lipoprotein-cholesterol varied 5-fold and was a linear function of the concentration of cholesteryl ester in the liver. These studies demonstrate that unsaturated FAs drive the esterification reaction and enhance lipoprotein cholesterol secretion by the liver under conditions where cholesterol balance across this organ is constant. Thus, individual FAs interact with cholesterol to profoundly regulate both the output and uptake of sterol by the liver, and these effects are articulated through the esterification reaction. The major determinant of atherosclerosis in any population appears to be the steady-state concentration of total cholesterol (TC) in the plasma and, more particularly, the concentration of cholesterol carried in low density lipoprotein (LDL-C) and other apolipoprotein B (apoB)-containing lipoprotein fractions. The incidence of death due to coronary artery disease (CAD), for example, increases in a nearly linear relationship to the plasma TC between values of approximately 150 mg/dl and 400 mg/dl (1The Expert PanelReport of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults.Arch. Intern. Med. 1988; 148: 36-69Google Scholar, 2Chen Z. Peto R. Collins R. MacMahon S. Lu J. Li W. Serum cholesterol concentration and coronary heart disease in populations with low cholesterol concentrations.BMJ. 1991; 303: 276-282Google Scholar). The relatively high concentration of circulating cholesterol and the high incidence of CAD seen in Western populations is related to the intake of both cholesterol and, particularly, triacylglycerol in these populations, although the manner in which these dietary constituents affect lipoprotein-cholesterol levels is still only partly understood. The steady-state concentration of LDL-C is determined by the rate at which this lipoprotein fraction is formed within the plasma space, i.e., the LDL-C production rate, the level of LDL receptor (LDLR) activity in the liver, and the amount of apoE-containing lipoprotein that is competing with LDL for binding to the LDLR (3Spady D.K. Dietschy J.M. Dietary saturated triacylglycerols suppress hepatic low density lipoprotein receptor activity in the hamster.Proc. Natl. Acad. Sci. USA. 1985; 82: 4526-4530Google Scholar, 4Spady D.K. Meddings J.B. Dietschy J.M. Kinetic constants for receptor-dependent and receptor-independent low density lipoprotein transport in the tissues of the rat and hamster.J. Clin. Invest. 1986; 77: 1474-1481Google Scholar, 5Meddings J.B. Dietschy J.M. Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man.Circulation. 1986; 74: 805-814Google Scholar, 6Woollett L.A. Spady D.K. Dietschy J.M. Mechanisms by which saturated triacylglycerols elevate the plasma low density lipoprotein-cholesterol concentration in hamsters. Differential effects of fatty acid chain length.J. Clin. Invest. 1989; 84: 119-128Google Scholar, 7Woollett L.A. Spady D.K. Dietschy J.M. Saturated and unsaturated fatty acids independently regulate low density lipoprotein receptor activity and production rate.J. Lipid Res. 1992; 33: 77-88Google Scholar, 8Woollett L.A. Osono Y. Herz J. Dietschy J.M. Apolipoprotein E competitively inhibits receptor-dependent low density lipoprotein uptake by the liver but has no effect on cholesterol absorption or synthesis in the mouse.Proc. Natl. Acad. Sci. USA. 1995; 92: 12500-12504Google Scholar). In general, of these three parameters, the most powerful determinant of the plasma LDL-C concentration in both animals and humans is the LDL-C production rate term (6Woollett L.A. Spady D.K. Dietschy J.M. Mechanisms by which saturated triacylglycerols elevate the plasma low density lipoprotein-cholesterol concentration in hamsters. Differential effects of fatty acid chain length.J. Clin. Invest. 1989; 84: 119-128Google Scholar, 7Woollett L.A. Spady D.K. Dietschy J.M. Saturated and unsaturated fatty acids independently regulate low density lipoprotein receptor activity and production rate.J. Lipid Res. 1992; 33: 77-88Google Scholar, 9Kesäniemi Y.A. Grundy S.M. Significance of low density lipoprotein production in the regulation of plasma cholesterol level in man.J. Clin. Invest. 1982; 70: 13-22Google Scholar). The rate of LDL-C production, however, is not an independent variable since the magnitude of this rate constant is determined by both the rate of secretion of cholesterol in very low density lipoprotein (VLDL-C) and the level of hepatic LDLR activity. This is true because a portion of the metabolized remnants of VLDL contains apoE and is removed from the circulation by the LDLR before it can be converted to LDL (10Yamada N. Shames D.M. Stoudemire J.B. Havel R.J. Metabolism of lipoproteins containing apolipoprotein B-100 in blood plasma of rabbits: heterogeneity related to the presence of apolipoprotein E.Proc. Natl. Acad. Sci. USA. 1986; 83: 3479-3483Google Scholar). As a consequence of this complex relationship, it is nearly impossible in the intact animal or human to explore how intracellular events in the liver influence the rate of VLDL-C secretion by simply quantitating changes in the LDL-C production rate. Hence, investigators have been forced to use either isolated cells or the perfused liver preparation in order to examine the regulation of hepatic VLDL assembly and secretion (11Johnson F.L. St. Clair R.W. Rudel L.L. Effects of the degree of saturation of dietary fat on the hepatic production of lipoproteins in the African green monkey.J. Lipid Res. 1985; 26: 403-417Google Scholar, 12Dixon J.L. Ginsberg H.N. Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins: information obtained from cultured liver cells.J. Lipid Res. 1993; 34: 167-179Google Scholar). Nevertheless, previous studies have shown that both dietary cholesterol and triacylglycerol are important in the regulation of the plasma LDL-C concentration and, further, several lines of evidence suggest that the microsomal enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) is key to this regulation. However, the manner in which this enzyme articulates the interaction between the dietary cholesterol and fatty acid (FA) reaching the liver, and the regulation of LDLR activity and VLDL-C secretion is poorly understood. Two isoforms of ACAT have recently been isolated (13Chang C.C.Y. Huh H.Y. Cadigan K.M. Chang T.Y. Molecular cloning and functional expression of human acyl-coenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells.J. Biol. Chem. 1993; 268: 20747-20755Google Scholar, 14Chang T.Y. Chang C.C.Y. Chen D. Acyl-coenzyme A:cholesterol acyltransferase.Annu. Rev. Biochem. 1997; 66: 613-638Google Scholar, 15Oelkers P. Behari A. Cromley D. Billheimer J.T. Sturley S.L. Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes.J. Biol. Chem. 1998; 273: 26765-26771Google Scholar, 16Cases S. Novak S. Zheng Y-W. Myers H.M. Lear S.R. Sande E. Welch C.B. Lusis A.J. Spencer T.A. Krause B.R. Erikson S.K. Farese Jr., R.V. ACAT-2, a second mammalian acyl-CoA:cholesterol acyltransferase. Its cloning, expression, and characterization.J. Biol. Chem. 1998; 273: 26755-26764Google Scholar, 17Anderson R.A. Joyce C. Davis M. Reagan J.W. Clark M. Shelness G.S. Rudel L.L. Identification of a form of acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates.J. Biol. Chem. 1998; 273: 26747-26754Google Scholar, 18Chang C.C.Y. Lee C.Y.G. Chang E.T. Cruz J.C. Levesque M.C. Chang T.Y. Recombinant acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) purified to essential homogeneity utilizes cholesterol in mixed micelles or in vesicles in a highly cooperative manner.J. Biol. Chem. 1998; 273: 35132-35141Google Scholar). In the mouse, ACAT-1 functions primarily in the adrenal gland and macrophage while in both the monkey and mouse, ACAT-2 is found primarily in the liver and intestine (17Anderson R.A. Joyce C. Davis M. Reagan J.W. Clark M. Shelness G.S. Rudel L.L. Identification of a form of acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates.J. Biol. Chem. 1998; 273: 26747-26754Google Scholar, 19Meiner V.L. Cases S. Myers H.M. Sande E.R. Bellosta S. Schambelan M. Pitas R.E. McGuire J. Herz J. Farese Jr., R.V. Disruption of the acyl-CoA:cholesterol acyltransferase gene in mice: Evidence suggesting multiple cholesterol esterification enzymes in mammals.Proc. Natl. Acad. Sci. USA. 1996; 93: 14041-14046Google Scholar, 20Meiner V. Tam C. Gunn M.D. Dong L-M. Weisgraber K.H. Novak S. Myers H.M. Erickson S.K. Farese Jr., R.V. Tissue expression studies on the mouse acyl-CoA:cholesterol acyltransferase gene (Acact): findings supporting the existence of multiple cholesterol esterification enzymes in mice.J. Lipid Res. 1997; 38: 1928-1933Google Scholar). This enzyme does not appear to be transcriptionally regulated but, rather, it responds to the supply of the two substrates, unesterified cholesterol and FA, presumably in the vicinity of the endoplasmic reticulum (ER) (21Chang C.C.Y. Chen J. Thomas M.A. Cheng D. Del Priore V.A. Newton R.S. Pape M.E. Chang T.Y. Regulation and immunolocalization of acyl-coenzyme A:cholesterol acyltransferase in mammalian cells as studied with specific antibodies.J. Biol. Chem. 1995; 270: 29532-29540Google Scholar, 22Uelmen P.J. Oka K. Sullivan M. Chang C.C.Y. Chang T.Y. Chan L. Tissue-specific expression and cholesterol regulation of acylcoenzyme A:cholesterol acyltransferase (ACAT) in mice.J. Biol. Chem. 1995; 270: 26192-26201Google Scholar, 23Matsuda H. Hakamata H. Miyazaki A. Sakai M. Chang C.C.Y. Chang T.Y. Kobori S. Shichiri M. Horiuchi S. Activation of acyl-coenzyme A:cholesterol acyltransferase activity by cholesterol is not due to altered mRNA levels in HepG2 cells.Biochim. Biophys. Acta. 1996; 1301: 76-84Google Scholar, 24Rea T.J. DeMattos R.B. Homan R. Newton R.S. Pape M.E. Lack of correlation between ACAT mRNA expression and cholesterol esterification in primary liver cells.Biochim. Biophys. Acta. 1996; 1299: 67-74Google Scholar). Based upon these observations, it has been postulated that in the steady state ACAT distributes excess sterol entering the liver between a pool of unesterified cholesterol in the ER and a pool of cholesteryl ester (22Uelmen P.J. Oka K. Sullivan M. Chang C.C.Y. Chang T.Y. Chan L. Tissue-specific expression and cholesterol regulation of acylcoenzyme A:cholesterol acyltransferase (ACAT) in mice.J. Biol. Chem. 1995; 270: 26192-26201Google Scholar). By suppressing the release of transcriptionally active sterol regulatory element-binding protein (SREBP) from the ER, this unesterified cholesterol suppresses hepatic LDLR activity (25Wang X. Sato R. Brown M.S. Hua X. Goldstein J.L. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis.Cell. 1994; 77: 53-62Google Scholar, 26Duncan E.A. Brown M.S. Goldstein J.L. Sakai J. Cleavage site for sterol-regulated protease localized to a Leu-Ser bond in the lumenal loop of sterol regulatory element-binding protein-2.J. Biol. Chem. 1997; 272: 12778-12785Google Scholar, 27Nohturfft A. Brown M.S. Goldstein J.L. Topology of SREBP cleavage-activitating protein, a polytopic membrane protain with a sterol-sensing domain.J. Biol. Chem. 1998; 273: 17243-17250Google Scholar). Increasing the flow of cholesterol into the hepatocyte progressively increases the size of these pools and proportionally reduces the activity of the LDLR. Thus, under conditions where the profile of FA in the liver is kept constant, hepatic LDLR activity varies inversely with the steady-state concentration of unesterified cholesterol in the ER and cholesteryl ester in the cell (28Erickson S.K. Shrewsbury M.A. Brooks C. Meyer D.J. Rat liver acyl-coenzyme A:cholesterol acyltransferase: its regulation in vivo and some of its properties in vitro.J. Lipid Res. 1980; 21: 930-941Google Scholar, 29Spady D.K. Dietschy J.M. Interaction of dietary cholesterol and triglycerides in the regulation of hepatic low density lipoprotein transport in the hamster.J. Clin. Invest. 1988; 81: 300-309Google Scholar, 30Spady D.K. Woollett L.A. Dietschy J.M. Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids.Annu. Rev. Nutr. 1993; 13: 355-381Google Scholar). This relationship is dramatically altered, however, when the liver is enriched with specific FAs that vary in their ability to be utilized by ACAT. Long chain-length saturated FAs, for example, suppress cholesteryl ester formation, force more unesterified cholesterol into the ER, and further suppress hepatic LDLR activity (7Woollett L.A. Spady D.K. Dietschy J.M. Saturated and unsaturated fatty acids independently regulate low density lipoprotein receptor activity and production rate.J. Lipid Res. 1992; 33: 77-88Google Scholar, 31Daumerie C.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. USA. 1992; 89: 10797-10801Google Scholar). In contrast, long chain-length unsaturated FAs, which are the preferred substrate for ACAT, shift cholesterol from the unesterified to the esterified pool and restore LDLR activity (31Daumerie C.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. USA. 1992; 89: 10797-10801Google Scholar). Thus, under conditions where the flow of sterol into the liver is kept constant, the content of specific FAs in the hepatocyte determines the distribution of intracellular cholesterol between the unesterified fraction in the ER and the cholesteryl ester pool. As a consequence, in this situation LDLR activity varies directly with the concentration of cholesteryl ester in the liver (3Spady D.K. Dietschy J.M. Dietary saturated triacylglycerols suppress hepatic low density lipoprotein receptor activity in the hamster.Proc. Natl. Acad. Sci. USA. 1985; 82: 4526-4530Google Scholar, 30Spady D.K. Woollett L.A. Dietschy J.M. Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids.Annu. Rev. Nutr. 1993; 13: 355-381Google Scholar, 31Daumerie C.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. USA. 1992; 89: 10797-10801Google Scholar, 32Woollett L.A. Spady D.K. Dietschy J.M. Regulatory effects of the saturated fatty acids 6:0 through 18:0 on hepatic low density lipoprotein receptor activity in the hamster.J. Clin. Invest. 1992; 89: 1133-1141Google Scholar). While these studies leave little doubt that the level of hepatic LDLR activity is determined by dietary cholesterol and FA acting in concert to regulate the concentration of unesterified cholesterol in the ER, there is less quantitative information on the consequence of altering the pool of cholesteryl ester on the rate of VLDL-C secretion and, ultimately, on the rate of LDL-C production. Thus, as the LDL-C production rate is the major determinant of the steady-state plasma LDL-C concentration, and as the VLDL-C secretion rate is an important determinant of the production of this atherogenic particle, these studies were undertaken to define the role of specific long chain-length FAs in regulating hepatic ACAT activity and the rate of cholesterol secretion in the VLDL particle. Specific experiments were designed 1) to establish a mouse model where the VLDL-C secretion rate could be measured in vivo, 2) to determine the dietary conditions under which net cholesterol balance across the liver was constant when specific FAs were fed, 3) to quantitate the effects of each of these single FAs on steady-state hepatic cholesteryl ester levels and rates of sterol secretion in VLDL, and 4) to determine the changes that take place in lipoprotein composition with the feeding of each of these FAs. These studies, therefore, provide the first detailed description of how each of these long chain-length fatty acids affect VLDL-C secretion, in vivo, and are complementary to data already published on how these same long chain-length FAs alter hepatic LDLR activity (30Spady D.K. Woollett L.A. Dietschy J.M. Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids.Annu. Rev. Nutr. 1993; 13: 355-381Google Scholar, 31Daumerie C.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. USA. 1992; 89: 10797-10801Google Scholar, 32Woollett L.A. Spady D.K. Dietschy J.M. Regulatory effects of the saturated fatty acids 6:0 through 18:0 on hepatic low density lipoprotein receptor activity in the hamster.J. Clin. Invest. 1992; 89: 1133-1141Google Scholar). These studies were carried out in a mouse model where the steady-state concentration of cholesterol in plasma apoB-containing lipoproteins was taken as a direct measure of the rate of hepatic cholesterol secretion in VLDL particles. The theoretical basis for this model was as follows. Unesterified and esterified cholesterol, triacylglycerol, and apoB are assembled in the liver and secreted into blood as VLDL. The rate of total cholesterol secretion by this mechanism in the steady state is the VLDL-C production rate, JVLDLC. After being metabolized in the periphery, a portion of the resulting VLDL remnants is cleared from the plasma by the LDLR while the remainder is converted to LDL-C at a velocity known as the LDL-C production rate ( JLDLC). Clearly, JLDLC can be influenced by changes in either JVLDLC or the level of LDLR activity. The LDL-C is also removed from the plasma by the LDLR located primarily in the liver (33Spady D.K. Turley S.D. Dietschy J.M. Receptor-independent low density lipoprotein transport in the rat in vivo. Quantitation, characterization, and metabolic consequences.J. Clin. Invest. 1985; 76: 1113-1122Google Scholar, 34Spady D.K. Huettinger M. Bilheimer D.W. Dietschy J.M. Role of receptor-independent low density lipoprotein transport in the maintenance of tissue cholesterol balance in the normal and WHHL rabbit.J. Lipid Res. 1987; 28: 32-41Google Scholar, 35Turley S.D. Spady D.K. Dietschy J.M. Role of liver in the synthesis of cholesterol and the clearance of low density lipoproteins in the cynomolgus monkey.J. Lipid Res. 1995; 36: 67-79Google Scholar, 36Osono Y. Woollett L.A. Herz J. Dietschy J.M. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.J. Clin. Invest. 1995; 95: 1124-1132Google Scholar) at a rate that is determined by the concentration of LDL-C in the plasma (CLDLC), and by the maximal transport velocity ( Jm) and apparent Michaelis constant (K m*) for the LDLR (4Spady D.K. Meddings J.B. Dietschy J.M. Kinetic constants for receptor-dependent and receptor-independent low density lipoprotein transport in the tissues of the rat and hamster.J. Clin. Invest. 1986; 77: 1474-1481Google Scholar, 37Meddings J.B. Dietschy J.M. Regulation of plasma low density lipoprotein levels: new strategies for drug design.in: Baulieu E. Forman D.T. Jaenicke L. Kellen J.A. Nagai Y. Springer G.F. Trager L. Will-Shahab L. Wittliff J.L. Progress in Clinical Biochemistry and Medicine. Volume 5. Springer-Verlag, Berlin.1987: 1-24Google Scholar). Because of competition from apoE-containing remnants, the K m* for LDL interacting with the LDLR is very high (∼100 mg/dl) in all species so that this transport process is never saturated under physiological conditions (4Spady D.K. Meddings J.B. Dietschy J.M. Kinetic constants for receptor-dependent and receptor-independent low density lipoprotein transport in the tissues of the rat and hamster.J. Clin. Invest. 1986; 77: 1474-1481Google Scholar, 5Meddings J.B. Dietschy J.M. Regulation of plasma levels of low-density lipoprotein cholesterol: interpretation of data on low-density lipoprotein turnover in man.Circulation. 1986; 74: 805-814Google Scholar, 8Woollett L.A. Osono Y. Herz J. Dietschy J.M. Apolipoprotein E competitively inhibits receptor-dependent low density lipoprotein uptake by the liver but has no effect on cholesterol absorption or synthesis in the mouse.Proc. Natl. Acad. Sci. USA. 1995; 92: 12500-12504Google Scholar). There is also a receptor-independent transport process that can remove LDL-C from the plasma at a rate designated P* (4Spady D.K. Meddings J.B. Dietschy J.M. Kinetic constants for receptor-dependent and receptor-independent low density lipoprotein transport in the tissues of the rat and hamster.J. Clin. Invest. 1986; 77: 1474-1481Google Scholar, 33Spady D.K. Turley S.D. Dietschy J.M. Receptor-independent low density lipoprotein transport in the rat in vivo. Quantitation, characterization, and metabolic consequences.J. Clin. Invest. 1985; 76: 1113-1122Google Scholar, 34Spady D.K. Huettinger M. Bilheimer D.W. Dietschy J.M. Role of receptor-independent low density lipoprotein transport in the maintenance of tissue cholesterol balance in the normal and WHHL rabbit.J. Lipid Res. 1987; 28: 32-41Google Scholar). Thus, under normal circumstances, the steady-state concentration of LDL-C in the plasma is given by the following expression (37Meddings J.B. Dietschy J.M. Regulation of plasma low density lipoprotein levels: new strategies for drug design.in: Baulieu E. Forman D.T. Jaenicke L. Kellen J.A. Nagai Y. Springer G.F. Trager L. Will-Shahab L. Wittliff J.L. Progress in Clinical Biochemistry and Medicine. Volume 5. Springer-Verlag, Berlin.1987: 1-24Google Scholar): However, when LDLR activity is abrogated, the Jm and K m* terms equal zero and this expression simplifies so that CLDLC becomes directly proportional to JLDLC /P*. Thus, as P* is not regulable (33Spady D.K. Turley S.D. Dietschy J.M. Receptor-independent low density lipoprotein transport in the rat in vivo. Quantitation, characterization, and metabolic consequences.J. Clin. Invest. 1985; 76: 1113-1122Google Scholar) in the absence of receptors, the concentration of cholesterol carried in the apoB-containing lipoproteins in the plasma is a direct, linear function of the rate of VLDL-C secretion from the liver in the steady state. This study, therefore, was largely carried out in mice lacking LDLR activity where the rate of cholesterol secretion from the liver could be judged directly from the concentration of sterol in the apoB-containing plasma lipoproteins. The mice used in these studies were all males and were either control animals with normal LDLR activity (LDLR+/+) or homozygous LDLR knockouts (LDLR−/−) (36Osono Y. Woollett L.A. Herz J. Dietschy J.M. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.J. Clin. Invest. 1995; 95: 1124-1132Google Scholar, 38Ishibashi S. Brown M.S. Goldstein J.L. Gerard R.D. Hammer R.E. Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.J. Clin. Invest. 1993; 92: 883-893Google Scholar). After weaning and genotyping, all experimental animals were fed ad libitum a cereal based, low cholesterol (0.02%, w/w), low fat (4.0%, w/w) rodent diet (No. 7001, Harlan Teklad, Madison, WI) until 3 months of age. The fatty acids in this diet have previously been described (39Turley S.D. Herndon M.W. Dietschy J.M. Reevaluation and application of the dual-isotope plasma ratio method for the measurement of intestinal cholesterol absorption in the hamster.J. Lipid Res. 1994; 35: 328-339Google Scholar). At 3-months, the mice were placed on the specific experimental diets for 3 weeks, after which the various measurements were carried out during the fed state at the mid-dark phase of the light cycle as described (36Osono Y. Woollett L.A. Herz J. Dietschy J.M. Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse.J. Clin. Invest. 1995; 95: 1124-1132Google Scholar). The experimental diets were formulated using triacylglycerols containing a single FA that included trioctanoate (FA 8:0), trimyristate (FA 14:0), trioleate (FA 18:1), and trilinoleate (FA18:2) (Sigma Chemical Co., St. Louis, MO, and Nu-Chek-Prep, Inc., Elysian, MN). Most experiments were carried out using four different diets that were designated as the FA 8:0, FA 14:0, FA 18:1, and FA 18:2 diets. These were all prepared using a meal form of rodent diet (No. 8604, Harlan Teklad) to which was added 0.2% cholesterol (w/w) and 5% FA 8:0 triacylglycerol (w/w). The four different experimental diets were then formulated from this common mixture by adding an additional 15% of the FA 8:0, FA 14:0, FA 18:1, and FA 18:2 triacylglycerol (w/w). In one experiment, the total triacylglycerol level of these four diets was kept constant at 20%, but the added cholesterol concentration was varied in increments from 0% to 1.0% (w/w). In another experiment, the meal form of the rodent diet was mixed with either no cholesterol or with 3% cholesterol (w/w) alone. Plasma was harvested from donor LDLR−/− mice maintained on the low cholesterol (0.02%, w/w) rodent diet (No. 7001, Harlan Teklad). The LDL fraction was isolated by preparative ultracentrifugation in the density range of 1.020–1.055 g/ml and then radiolabeled with either 125I-cellobiose (TCB) or 131I (35Turley S.D. Spady D.K. Dietschy J.M. Role of liver in the synthesis of cholesterol and the clearance of low density lipoproteins in the cynomolgus monkey.J. Lipid Res. 1995; 36: 67-79Google Scholar, 40Glass C.K. Pittman R.C. Keller G.A. Steinbern D. Tissue sites of degradation of apoprotein A-I in the rat.J. Biol. Chem. 1983; 258: 7161-7167Google Scholar, 41Turley S.D. Spady D.K. Dietschy J.M. Identification of a metabolic difference accounting for the hyper- and hyporesponder phenotypes of cynomolgus monkey.J. Lipid Res. 1997; 38: 1598-1611Google Scholar). These labeled LDL fractions were contaminated with small amounts of apoE-containing HDL, which were removed by passing the lipoprotein solution over a heparin sepharose CL-6B column (Pharmacia Biotech, Uppsala, Sweden) (42Weisgraber K.H. Mahley R.W. Subfraction of human high density lipoprotein by heparin-sepharose affinity chromatography.J. Lipid Res. 1980; 21: 316-325Google Scholar). After dialysis, these radiolabeled preparations were passed through a 0.45 μm Millex-HA filter (Millipore Products, Bedford, MA) immediately prior to injection into the recipient experimental animal. All fractions were used within 48 h of preparation. Mice were lightly anesthetized with diethyl ether and then given xylazine-20 (Butler Company, Columbus, OH) subcutaneously, and a catheter was inserted into a jugular vein. After awakening, each animal was given a bolus of 125I-TCB-labeled LDL followed by a continuous infusion of the same preparation at a rate calculated to maintain a constant specific activity in the plasma. Five minutes before the termination of the 4 h infusion period, a bolus of 131I-LDL was administered to each of the animals. The animals were exsanguinated at 4 h and the liver was removed. The remaining carcass was cut into small pieces. Liver, carcass, and plasma samples were assayed for their content of 125I and 131I. These were used to calculate a rate of clearance of LDL by the liver and carcass. These clearance rates were expressed as the ml of plasma cleared of its LDL content per day per liver or carcass per kg body weight (ml/d per kg). Each animal was injected ip with approximately 20 mCi of [3H]water and, after 1 h, was anesthetized and exsanguinated. Aliquots of plasma were taken for measurement of the specific activity of the plasma water. The liver and remaining carcass were saponified and digitonin-precipitable sterols (DPS) were isolated as described (35Turley S.D. Spady D.K. Dietschy J.M." @default.
• W2142267239 created "2016-06-24" @default.
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• W2142267239 date "2002-09-01" @default.
• W2142267239 modified "2023-10-18" @default.
• W2142267239 title "Fatty acids differentially regulate hepatic cholesteryl ester formation and incorporation into lipoproteins in the liver of the mouse" @default.
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