Bile Acids Regulate Hepatic Low Density Lipoprotein Receptor Activity in The

Home , Chenodeoxycholic acid, Cholic acid

Proc. Natl. Acad. Sci. USA Vol. 83, pp. 1916-1920, March 1986 Medical Sciences Bile acids regulate hepatic low density lipoprotein receptor activity in the hamster by altering cholesterol flux across the liver (cholesterol synthesis/cholesteryl esters/chenodeoxycholic acid/ursodeoxycholic acid/cholic acid) DAVID K. SPADY, EDUARD F. STANGE, LYMAN E. BILHARTZ, AND JOHN M. DIETSCHY Department of Internal Medicine, University of Texas Health Science Center at Dallas, Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75235 Communicated by Jean D. Wilson, November 18, 1985

ABSTRACT The effect of different bile acids on receptor- found in the liver (3, 6, 7). Therefore, changes in circulating dependent and receptor-independent low density lipoprotein LDL levels associated with bile acid feeding almost certainly (LDL) uptake in the liver and intestine was investigated. When reflect a change in either hepatic LDL receptor activity or the fed at the 0.1% level for three weeks, cholic acid and rate of LDL synthesis. chenodeoxycholic acid suppressed hepatic cholesterol synthesis Bile acids might effect LDL catabolism by acutely altering in the rat by 80% and 50%, respectively, while ursodeoxycholic the rate of receptor-dependent LDL transport in the liver. acid had no effect. In contrast, hepatic cholesteryl ester levels, Indeed, it has been reported that a 4-6 hr infusion of rates of hepatic LDL transport, and concentrations of plasma taurocholic acid completely abolishes specific LDL binding LDL-cholesterol were not affected by bile acid feeding in this to liver membranes in the dog (8). On the other hand, more species. Cholic acid and chenodeoxycholic acid also suppressed chronic administration of bile acids could change LDL hepatic cholesterol synthesis in the hamster. However, since metabolism indirectly by altering cholesterol balance across basal rates of hepatic cholesterol synthesis in this species, as in the liver. For example, it is well recognized that cholic acid man, are very low, the absolute reduction in hepatic synthesis and chenodeoxycholic acid promote cholesterol absorption could not compensate for the change in hepatic sterol balance from the intestine and suppress bile acid synthesis in the liver induced by bile acid feeding. Hence, in the hamster the feeding more effectively than does ursodeoxycholic acid (9-14). Both of cholic acid and chenodeoxycholic acid increased hepatic effects would tend to increase the available pool of choles- cholesteryl ester levels 660% and 39%, respectively, reduced terol within the hepatocyte. This, in turn, would lead to a hepatic receptor-dependent LDL uptake by 50% and 32%, reduction in the rate of de novo synthesis and, if this respectively, and elevated plasma LDL-cholesterol levels by reduction were quantitatively inadequate to compensate for 160% and 50%, respectively. Ursodeoxycholic acid feeding did the increased sterol pool, a reduced rate of LDL-cholesterol not alter any of these processes, and none of the bile acids uptake from the plasma. changed the rate of hepatic receptor-independent LDL trans- The present studies were, therefore, undertaken to exam- port. In the intestine, none of the bile acids altered rates of ine the effect of bile acid feeding on LDL transport and cholesterol synthesis or LDL uptake. When cholic acid, cholesterol synthesis in the liver and small intestine and to chenodeoxycholic acid, or ursodeoxycholic acid was infused determine if such effects were due to the direct regulation of continuously for 8 hr in supranormal amounts into control these two metabolic pathways by bile acids or to a compen- hamsters or rats or into animals pretreated with cholestyra- satory response to alterations in cholesterol balance across mine, there were no changes in LDL transport or any other the liver. These studies were carried out in vivo in the rat, parameter of hepatic cholesterol metabolism. Thus, these which can alter its rate of hepatic cholesterol synthesis over studies indicated that cholic acid and chenodeoxycholic acid a very wide range (3), and in the hamster, which, like man, have no acute, direct effect on rates ofreceptor-dependent LDL is much more limited in this regard and responds to changes transport or cholesterol synthesis but do alter these processes in cholesterol balance and other dietary manipulations with a indirectly by inducing changes in cholesterol balance across the change in circulating plasma LDL-cholesterol levels (6, 7, liver. Ursodeoxycholic acid, in contrast, does not affect these 15). processes either directly or indirectly and so causes no change in plasma LDL levels. MATERIALS AND METHODS The use of chenodeoxycholic acid and ursodeoxycholic acid Animals and Diets. Female Sprague-Dawley rats and male in the medical treatment of cholesterol gallstone disease has Golden Syrian hamsters (Charles River Breeding Laborato- lead to renewed interest in the effects of chronic bile acid ries) were light cycled and fed a control rodent diet (Allied administration on cholesterol and lipoprotein metabolism. Mills, Chicago) for 3 weeks prior to use. At that time the rats That bile acids play a regulatory role in lipoprotein metabo- and hamsters weighed 180-220 g and 110-140 g, respectively. lism is suggested by the finding that the administration of The experimental diets were prepared by mixing 0.1% chenodeoxycholic acid, but not ursodeoxycholic acid, leads (wt/wt) cholic acid, chenodeoxycholic acid, and ursodeoxy- to a gradual increase in plasma low density lipoprotein (LDL) cholic acid with ground rodent diet, following which the diet levels in man (1, 2). A major determinant of plasma LDL was repelleted. Each diet was fed ad libitum to different levels is the rate at which LDL is removed from the plasma groups of animals for 3 weeks. Weight gain over the feeding and degraded. In most species, including man, approximately period was not significantly different in any of the groups. At 70% of total LDL catabolism is receptor dependent (3-5). the end ofthis 3-week period, all experimental measurements Furthermore, in all species examined 80-90% ofthe receptor- were carried out during the mid-dark phase of the light cycle. dependent LDL transport activity demonstrable in vivo is Determination of Sterol Synthesis Rates in Vivo. As described (16-18), animals were administered 3H20 (approximately 50 mCi; 1 Ci = 37 GBq) intravenously and killed 1 hr The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. Abbreviations: LDL, low density lipoprotein. 1916 Downloaded by guest on September 26, 2021 Medical Sciences: Spady et al. Proc. Natl. Acad. Sci. USA 83 (1986) 1917

later. Aliquots of plasma were taken for the determination of and prepurified by using a Sep-Pak cartridge (Waters Asso- plasma water specific activity, and aliquots of liver were ciates). HPLC analysis was then performed by using a Waters obtained for the isolation of digitonin precipitable sterols. Associates system with a differential refractometer and a The entire small intestine was saponified, and aliquots also ,uBondapak C18 reversed-phase column. The mobile phase were taken for the isolation of sterols. Rates of synthesis used was methanol/water/glacial acetic acid (73:25:2, were expressed as the nmol of 3H20 incorporated into vol/vol) adjusted to a pH of4.5 with NaOH and run at a pump digitonin precipitable sterols per hr per g of tissue (nmol/hr speed of 1.3 ml/min. per g). Lipoprotein Preparation. Rat, hamster, and human LDL RESULTS was isolated from plasma by preparative ultracentrifugation in the density range of 1.020-1.055 g/ml and labeled with Preliminary studies were done to determine the effects ofbile ["4C]sucrose (Amersham) (19). The hamster and human LDL acid feeding at the 0.1% level on total plasma cholesterol in this density range contained almost exclusively apolipo- concentrations and on bile acid pool sizes and composition in protein B-100 on polyacrylamide gels. Rat LDL, however, the rat and hamster. As summarized in Table 1, in control rats contained significant amounts of apolipoprotein E and re- the plasma cholesterol level equaled 56 mg/dl and was not quired further purification on Geon-Pevikon slabs (20). The affected by bile acid feeding. In control hamsters, the plasma human LDL was methylated as described (21). All lipopro- cholesterol level equaled 115 mg/dl and increased signifi- tein fractions were used within 24 hr of preparation and were cantly with cholic acid (51%) and chenodeoxycholic acid filtered through a 0.45-,um pore sized Millipore filter imme- (23%) feeding. In contrast, ursodeoxycholic acid had no diately prior to use. effect. The total bile acid pool size increased only marginally Determination of Tissue LDL Uptake Rates in Vivo. Rates of in the bile acid fed rats but increased approximately 50% in tissue LDL clearance were determined by using a primed- all three groups of bile acid fed hamsters. In the rats, the continuous infusion of [14C]sucrose-labeled LDL (3, 6). major bile acids were cholic acid, muricholic acid, and Groups of animals were killed at 10 min, 2 hr, 4 hr, and 6 hr chenodeoxycholic acid. With bile acid feeding, the fed bile by exsanguination through the abdominal aorta, and aliquots acid accounted for 80%, 31%, and 37% of the total bile acid of plasma and tissue were obtained and solubilized (6, 22). pool in the rats given cholic acid, chenodeoxycholic acid, and The radioactivity in the liver and small intestine at each time ursodeoxycholic acid, respectively. In control hamsters the point was expressed as the number of ,l ofplasma that would major bile acids were cholic acid and chenodeoxycholic acid, contain an equivalent amount of radioactivity. The increase and in hamsters fed the various bile acids, the fed bile acid in this tissue space with time equaled the number of ,ul of accounted for >70% of the total bile acid pool. plasma cleared entirely of its LDL content per hr per g wet Studies were next undertaken to examine the effects ofbile weight of tissue (,l/hr per g). When these clearance values acid feeding on rates of cholesterol synthesis and LDL were multiplied by the plasma LDL-cholesterol concentra- transport in the liver. As has been noted (18), the liver of tion, the absolute rate of LDL-cholesterol uptake was control rats synthesized cholesterol at the very high rate of obtained (,ug/hr per g). approximately 2000 nmol/hr per g, as shown in Fig. LA. Analytic Procedures. Plasma LDL-cholesterol concentra- Cholic acid and chenodeoxycholic acid feeding suppressed tions (density of 1.020-1.063 g/ml) were measured colori- the rate of hepatic synthesis by nearly 80% and 50%, metrically (23). Hepatic free and esterified cholesterol levels respectively, while ursodeoxycholic acid had no effect. were measured by using silicic acid/celite columns as de- However, despite these effects on synthesis, none of the bile scribed (24). The total content of bile acids extractable from acids significantly altered hepatic cholesteryl ester levels the intestine and liver was assayed by using the 3a- (Fig. 1B), hepatic LDL clearance rates (Fig. 1C), or plasma hydroxysteroid dehydrogenase assay described (25), and LDL-cholesterol concentrations (Fig. 1D) in this species. these total pools were expressed as the ,umol of bile acid per In the hamster, the relative changes in rates of hepatic kg of body weight. To identify the individual bile acids cholesterol synthesis induced by bile acid feeding were present in this pool, aliquots were also diluted with 100 mM similar to those found in the rat in that cholic acid and NaOH, filtered through a 0.45-,um pore size Millipore filter chenodeoxycholic acid inhibited synthesis by approximately

Table 1. Plasma cholesterol concentration and the composition of the bile acid pool in rats and hamsters fed different bile acids Plasma cholesterol Bile acid pool Bile acid concentration, Total, MCA, UDCA, CA, CDCA, DCA, LCA, fed mg/dl timol/kg % %t % % % Rat Control 56 ± 3 565 ± 26 31 4 48 14 3 * CA 54 ± 2 620 ± 42 lit 1 80t 3t 5t CDCA 53 ± 4 594 ± 21 37 8t 22t 31t 1 UDCA 57 ± 4 628 ± 42 21t 37t 28t 12 1 Hamster Control 115± 6 128 ± 17 72 22 5 CA 174 101ot 212 ± 17t 74 it 24t CDCA 141± 9t 189 ± 15 - 7t 87t 2 4 UDCA 112 ± 5 198 ± 8t 70t lot 15 3 2 Groups of six animals were fed either control diet or this same diet containing 0.1% (wt/wt) cholic acid (CA), chenodeoxycholic acid (CDCA), or ursodeoxycholic acid (UDCA) for three weeks. Mean values ± 1 SEM are shown for the plasma cholesterol concentrations and total bile acid pool sizes. Only mean values are given for the percentage distribution of the individual bile acids in each pool. LCA, lithocholic acid; MCA, muricholic acid; DCA, deoxycholic acid. *Dashes indicate that a particular bile acid represented <1% of the total bile acid pool. tSignificantly different (P < 0.05) from the appropriate control value. Downloaded by guest on September 26, 2021 1918 Medical Sciences: Spady et al. Proc. Natl. Acad. Sci. USA 83 (1986) The effect of bile acid feeding on rates of cholesterol 2000B -.0 W synthesis and LDL clearance in the small intestine of these °2000pAid i 511 -J] animals also was measured, and the results are summarized 0Z~~~~~~~~I ~ ~ ~ ~ in Fig. 3. The rate of cholesterol synthesis in the small QU) hd intestine was unaffected by bile acid feeding in either the rat (Fig. 3A) or the hamster (Fig. 3C). In the rat, the rate of LDL W c) 5500L Ai2Oc clearance in the small intestine also was unaffected (Fig. 3B); however, in the hamster the rate of LDL clearance in the small intestine was modestly decreased by cholic acid and chenodeoxycholic acid feeding but remained unchanged with c X 060 eE ursodeoxycholic acid (Fig. 3D). c M 10 0* Since plasma LDL cholesterol concentrations were elevated in the hamsters fed chenodeoxycholic acid and cholic acid, it was impossible to interpret whether the observed decreases in LDL clearance reflected an increase in the (4 production rate of LDL and increased saturation of LDL (410 M 1. receptors, or actual suppression of receptor-dependent LDL transport. To distinguish these two possibilities, the kinetic FIG. 1. Hepatic cholesterol synthesis (A), hepatic cholesteryl characteristics of the receptor-dependent and receptor-inde- ester content (B), hepatic LDL clearance (C), and plasma LDL-cho- pendent transport processes in the liver and small intestine lesterol concentration (D) in rats fed rodent diet alone (controls) or were defined over the range of plasma LDL-cholesterol rodent diet plus 0.1% cholic acid (CA), chenodeoxycholic acid concentrations seen in the bile acid fed animals. Thus, rates (CDCA) or ursodeoxycholic acid (UDCA) for 3 weeks. Each value of LDL clearance were measured in control hamsters whose represents the mean + 1 SEM for data obtained in 6 rats. plasma LDL-cholesterol levels were acutely raised and maintained at values ranging from 25 mg/dl to 100 mg/dl by 65% and 45%t, respectively. However, as shown in Fig. 2A, adding various amounts of unlabeled LDL to the primed- the absolute rate of hepatic cholesterol synthesis in control continuous infusions of ["4C]sucrose-labeled LDL. Such hamsters was only one-fiftieth of that in control rats. Thus, studies were performed by using both homologous LDL (to the absolute reductions in hepatic cholesterol synthesis seen measure total LDL transport) and methylated human LDL in the hamsters fed cholic acid and chenodeoxycholic acid (to measure receptor-independent transport) (6, 7, 15). The were quantitatively trivial and could not compensate for any data were analyzed by using least-square, nonlinear regres- significant change in cholesterol flux induced by bile acid sion methods as described (15), and the best-fit curves ± 2 SD feeding. Thus, in these animals the hepatic cholesteryl ester are presented in Fig. 4 in two different ways. Fig. 4 A and C levels increased by 660% and 39%, respectively, with cholic show the relationship between total LDL clearance (stippled acid and chenodeoxycholic acid feeding (Fig. 2B). Further- areas) and receptor-independent clearance (hatched areas) more, cholic acid and chenodeoxycholic acid suppressed the and the plasma LDL-cholesterol concentration in both the rate of hepatic LDL clearance by 58% and 36% (Fig. 2C), liver (A) and small intestine (C). These same data are respectively, and this was associated with an increase in presented in Fig. 4B and D as total and receptor-independent plasma LDL-cholesterol levels of 160% and 50%t (Fig. 2D), LDL-cholesterol uptake. In both cases the areas between the respectively. As in the rat, ursodeoxycholic acid had no two curves represent the receptor-dependent component of effect on any parameter of hepatic cholesterol metabolism LDL transport. The observed rates of LDL transport in the even though it expanded the bile acid pool to a similar degree bile acid fed hamsters are superimposed upon these standard as seen with cholic acid and chenodeoxycholic acid feeding LDL in animals. (Table 1). kinetic curves for transport control

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FIG. 2. Hepatic cholesterol synthesis (A), hepatic cholesteryl ester content (B), hepatic LDL clearance (C), and plasma LDL- FIG. 3. Intestinal cholesterol synthesis (A and C) and LDL cholesterol concentrations (D) in hamsters fed rodent diet alone clearance (B and D) in rats and hamsters fed rodent diet alone (controls) or rodent diet plus 0.1% cholic acid (CA), chenodeoxy- (controls) or rodent diet plus 0.1% cholic acid (CA), chenodeoxycholic acid (CDCA), or ursodeoxycholic acid (UDCA) for 3 weeks. cholic acid (CDCA), or ursodeoxycholic acid (UDCA) for 3 weeks. Each value represents the mean ± 1 SEM for data obtained in 6 Each value represents the mean + 1 SEM for data obtained in 6 hamsters. .... animals. Downloaded by guest on September 26, 2021 Medical Sciences: Spady et al. Proc. Natl. Acad. Sci. USA 83 (1986) 1919

SMALL cholesterol synthesis and LDL transport could be detected. LIVER INTESTINE Rats and hamsters were placed in restraining cages and C administered an intravenous infusion of the taurine conju- f75 A Fe CONTROL TOTAL -DL O UDCA gates of cholic acid and chenodeoxycholic acid (100 gmol/hr 1! TRANSPORT 40 * CDCA per kg of body weight) for 8 hr at which time rates of hepatic 125~~~~~~ YOCA cholesterol and LDL were determined in w synthesis transport I 30r\2 vivo. In these studies, no suppression was observed in either 11100 2 hepatic cholesterol synthesis or hepatic LDL transport in the )-J animals infused with cholic acid or chenodeoxycholic acid. 75 + 20k Even when the animals were pretreated with cholestyramine 50 1 (3%, wt/wt) for 10 days to derepress rates of hepatic 0r RECEPTOR- INDEPENDENT, cholesterol synthesis (rats and hamsters) and LDL transport 25- TRANSPORT (hamsters), there was no suppression of hepatic cholesterol < LU 25 - synthesis or LDL transport by the 8 hr infusion of cholic acid or chenodeoxycholic acid. X 25 07 O 00 I100 75_ DISCUSSION 50 7 These studies demonstrate that chronic cholic acid and 10- chenodeoxycholic acid feeding in the hamster suppresses 25 5 hepatic receptor-dependent LDL transport by 50% and 32%, respectively, while the rate of receptor-independent trans- 25 50 75 100 port remains unchanged. In the hamster, as well as in the PLASMA LDL-CHOLESTEROL other species that have been studied, the liver is the major site CONCENTRATION (mg/dl) for LDL catabolism (3, 6). Furthermore, the uptake of LDL FIG. 4. LDL clearance (A and C) and LDL-cholesterol uptake (B by the liver is mediated largely (>90%) by LDL receptors (6, and D) in the liver and small intestine of hamsters fed rodent diet 7, 15). Thus, a change in hepatic receptor-dependent trans- alone (e) or rodent diet plus 0.1% cholic acid (CA, o), port would be expected to have a major effect on LDL levels chenodeoxycholic acid (CDCA, *), or ursodeoxycholic acid (UDCA, and, indeed, plasma LDL-cholesterol concentrations in- o) for 3 weeks. The shaded areas represent the kinetic curves (± 2 creased 160% and 50% in hamsters fed cholic acid and SD) for total (stippled) and receptor-independent (hatched) LDL chenodeoxycholic acid, respectively. However, the intrave- transport in normal hamsters. The experimental values are super- nous infusion of these two bile acids at rates 50% to 100% imposed on these standard transport curves, and each point repre- higher than the normal flux across the liver failed to alter sents the mean ± 1 SEM for data obtained in 6 animals. hepatic LDL transport even after 8 hr in the hamster and rat, and this was true even under circumstances where hepatic As seen in Fig. 4A, rates of hepatic LDL clearance in LDL transport and cholesterol biosynthesis had been in- hamsters fed cholic acid and chenodeoxycholic acid fell creased by pretreatment with cholestyramine. These latter significantly below the rates of hepatic LDL transport that findings, therefore, differ significantly from a previous report would be expected in control hamsters at similar plasma LDL that specific LDL binding to hepatic membranes in the dog concentrations. Although the data are not shown, rates of was abolished by the intravenous administration of tauro- methylated human LDL clearance (receptor-independent cholate for 4-6 hr (8) and suggest that there is no acute, direct transport) in the liver were not affected by cholic acid or effect ofthese two bile acids on the receptor-dependent LDL chenodeoxycholic acid feeding. Thus, it can be calculated transport process. that the rate of receptor-dependent LDL transport in the liver In contrast to these results observed with cholic acid and was suppressed 50% and 32% by cholic acid and chenode- chenodeoxycholic acid, the chronic feeding of ursodeoxy- oxycholic acid feeding, respectively. In Fig. 4B the absolute cholic acid had no effect on hepatic LDL uptake or plasma rates of LDL-cholesterol uptake in the liver were calculated LDL levels. Since the regulation ofcholesterol metabolism in by multiplying the clearance rates shown in Fig. 4A by the the hamster very closely reflects regulation in man, these plasma LDL-cholesterol concentrations found in the same findings presumably explain the gradual rise in plasma animals. It is apparent that the absolute rates of LDL-cho- LDL-cholesterol levels that have been reported in patients lesterol uptake were essentially the same in all four experi- undergoing gallstone dissolution therapy with chenodeoxy- mental groups. In the case of chenodeoxycholic acid and, cholic acid but not in those receiving ursodeoxycholic acid particularly, cholic acid feeding this was accomplished by (1). allowing the plasma LDL-cholesterol concentration to rise In theory, these effects of chronic bile acid administration and utilizing the receptor-independent component of LDL could have resulted from a direct action ofthe bile acid on the uptake to a greater extent. The findings were quite different genetic regulation of the LDL receptor or, alternatively, in the intestine in that the rates of LDL clearance (Fig. 4C) could have arisen indirectly through an effect on net choles- and LDL-cholesterol uptake (Fig. 4D) observed in the bile terol balance across the cell. Two lines of evidence suggest acid fed groups were superimposable upon the standard that the latter possibility is correct and that regulation of kinetic curves for LDL transport in control animals. Hence, receptor-dependent LDL transport is mediated by a change whereas chenodeoxycholic acid and cholic acid feeding in the size of some critical, regulatory pool of sterol in the suppressed receptor-dependent LDL transport in the liver, liver. First, certain bile acids may alter cholesterol flux no such suppression was observed in the intestine. Rather, across the liver by both promoting sterol absorption from the the reduction in LDL clearance observed in the intestine of intestine and suppressing the conversion ofcholesterol to bile the hamsters fed chenodeoxycholic acid and cholic acid (Fig. acids. Cholic acid and, to a lesser extent, chenodeoxycholic 3D) merely reflected the rise in plasma LDL-cholesterol acid can exert both of these effects while ursodeoxycholic levels and further saturation, but not suppression, of LDL- acid may actually lower dietary sterol absorption and has receptor transport in the intestine. little effect on regulation of bile acid synthesis (9-14). Thus A final group of experiments was performed to determine the differential effects of these three bile acids on LDL if an acute, direct effect of these two bile acids on hepatic metabolism in the hamster closely reflect their known effects Downloaded by guest on September 26, 2021 1920 Medical Sciences: Spady et al. Proc. Mid. Acad Sci. USA 83 (1986) on hepatic sterol balance. Second, the liver ofthe rat has such 3. Spady, D. K., Turley, S. D. & Dietschy, J. M. (1985) J. Lipid an exceptionally high rate of sterol synthesis that the 80% Res. 26, 465-472. suppression seen with cholic acid feeding (Fig. 1) resulted in 4. Bilheimer, D. W., Watanabe, Y. & Kita, T. (1982) Proc. Natl. Acad. Sci. USA 79, 3305-3309. a decrease in cholesterol production by the liver equal to 5. Kesaniemi, Y. A., Witztum, J. L. & Steinbrecher, U. P. about 50 ,ug/hr per g. Presumably this fully compensates for (1983) J. Clin. Invest. 71, 950-959. any change that may have occurred in hepatic cholesterol 6. Spady, D. K., Bilheimer, D. W. & Dietschy, J. M. (1983) acquisition due to enhanced cholesterol absorption or re- Proc. Natl. Acad. Sci. USA 80, 3499-3503. duced conversion to bile acids. However, the similar per- 7. Spady, D. K., Turley, S. D. & Dietschy, J. M. (1985) J. Clin. centage decrease in cholesterol synthesis induced by cholic Invest. 76, 1113-1122. acid feeding in the hamster (Fig. 2) resulted in an absolute 8. Angelin, B. C., Riviola, A., Innerarity, T. L. & Mahley, R. W. decrease in cholesterol synthesis of only 1 pug/hr per g. (1983) J. Clin. Invest. 71, 816-831. in the liver as esters and 9. Leiss, O., von Bergmann, K., Streicher, U. & Strotkoetter, H. Hence, cholesterol accumulated (1984) Gastroenterology 87, 144-149. receptor-dependent LDL transport was suppressed. Thus, 10. Ponz De Leon, M., Carulli, N., Loria, P., Iori, R. & Zironi, F. whether or not bile acid feeding causes changes in the rate of (1979) Gastroenterology 77, 223-230. receptor-dependent LDL transport appears to depend on 11. Raicht, R. F., Cohen, B. I., Sarwal, A. & Takahashi, M. whether or not the liver of a particular species can compen- (1978) Biochim. Biophys. Acta 531, 1-8. sate fully for a change in cholesterol flux across that organ by 12. Raicht, R. F. & Cohen, B. I. (1974) Gastroenterology 67, an appropriate change in the rate of cholesterol synthesis. 1155-1161. Finally, the effect ofcholic acid and chenodeoxycholic acid 13. Hardison, W. G. M. & Grundy, S. M. (1984) Gastroenterol- feeding was exerted only in the liver and manifested by ogy 87, 130-135. LDL uptake in that organ. The 14. von Bergmann, K., Epple-Gutsfeld, M. & Leiss, 0. (1984) reduced receptor-dependent Gastroenterology 87, 136-143. secondary increase in circulating LDL concentrations, how- 15. Spady, D. K. & Dietschy, J. M. (1985) Proc. Natl. Acad. Sci. ever, did not result in suppression of receptor-dependent USA 82, 4526-4530. LDL transport in the extrahepatic tissues, as was evident in 16. Jeske, D. J. & Dietschy, J. M. (1980) J. Lipid Res. 21, the intestine (Fig. 4). A similar finding has been reported with 364-376. cholestyramine feeding in that LDL transport was increased 17. Turley, S. D., Andersen, J. M. & Dietschy, J. M. (i981) J. in the liver but not in the extrahepatic organs (6). Thus, Lipid Res. 22, 551-569. manipulations such as bile acid and cholestyramine feeding 18. Spady; D. K. & Dietschy, J. M. (i983) J. Lipid Res. 24, affect receptor-dependent LDL transport only in the liver. 303-315. 19. Pittman, R. C., Green, S. R., Attie, A. D. & Steinberg, D. These studies were supported by U.S. Public Health Service (1979) J. Biol. Chem. 254, 6876-6879. Research Grants HL-09610 and AM-19329 and by a grant from the 20. Mahley, R. W. & Weisgraber, K. H. (1974) Biochemistry 13, Moss Heart Fund. In addition, D.K.S. was supported by U.S. Public i964-1969. Health Service Grant AM-01221 and American Heart Association, 21. Mahley, R. W., Weisgraber, H., Melchior, G. W., Innerarity, Texas Affiliate Grant G155. E.F.S. was supported by a grant from the T. L. & Holcombe, K. S. (1980) Proc. Natl. Acad. Sci. USA Deutsche Forschungsgemeinschaft, add L.E.B. was supported by 77, 225-229. U.S. Public Health Service Training Grant AM-07100 and an Amer- 22. Munford, R. S., Andersen, J. M. & Dietschy, J. M. (1981) J. ican Liver Foundation grant. Clin. Invest. 68, 1503-1513. 23. Tonks, D. B. (1967) Clin. Biochem. 1, 12-29. 1. Schoenfield, L. J. & Lachin, J. M. (1981) Ann. Intern. Med. 24. Andersen, J. M. & Dietschy, J. M. (1978) J. Biol. Chem. 253, 95, 257-282. 9024-9032. 2. Erlinger, S., Le Go, A., Husson, J.-M. & Fevery, J. (1984) 25. Turley, S. D. & Dietschy, J. M. (1978) J. Lipid Res. 19, Hepatology (Baltimore) 4, 2308-2324. 924-928. Downloaded by guest on September 26, 2021