Effect of ursodeoxycholic acid on cholesterol absorption and metabolism in humans

Qualitative and quantitative changes in intraluminal bile acid composition may alter cholesterol absorption and synthesis and LDL receptor expression. In a randomized crossover design outpatient study, 12 adults aged 24–36 years took 15 mg/kg/day ursodeoxycholic acid (UDCA) or no bile acid supplement (control) for 20 days while being fed a controlled diet (AHA Step II). A liquid meal of defined composition was then given and luminal samples collected. Cholesterol absorption and cholesterol fractional synthetic rate (FSR) were assessed by stable isotopic methods. With UDCA treatment, bile was enriched significantly (P < 0.0001) to 40.6 ± 2.6% (mean ± SEM) compared with 2.2 ± 2.6% for controls. Regardless, plasma total, HDL, and LDL cholesterol were unchanged with UDCA treatment. Intraluminal cholesterol solubilized in the aqueous phase during the entire collection was decreased (P = 0.012) in UDCA-treated subjects (101.0 ± 7.2 mg/ml/120 min) compared with controls (132.5 ± 7.2 mg/ml/120 min.). Percent micellar cholesterol was increased in UDCA-treated versus controls after meal ingestion. No changes were found in cholesterol absorption, FSR, or LDL receptor mRNA with UDCA treatment compared with controls.Thus, despite marked enrichment in luminal bile with UDCA and decreased cholesterol solubilization, no differences in cholesterol absorption or metabolism are found when diet and genetic differences in absorption are carefully controlled. Qualitative and quantitative changes in intraluminal bile acid composition may alter cholesterol absorption and synthesis and LDL receptor expression. In a randomized crossover design outpatient study, 12 adults aged 24–36 years took 15 mg/kg/day ursodeoxycholic acid (UDCA) or no bile acid supplement (control) for 20 days while being fed a controlled diet (AHA Step II). A liquid meal of defined composition was then given and luminal samples collected. Cholesterol absorption and cholesterol fractional synthetic rate (FSR) were assessed by stable isotopic methods. With UDCA treatment, bile was enriched significantly (P < 0.0001) to 40.6 ± 2.6% (mean ± SEM) compared with 2.2 ± 2.6% for controls. Regardless, plasma total, HDL, and LDL cholesterol were unchanged with UDCA treatment. Intraluminal cholesterol solubilized in the aqueous phase during the entire collection was decreased (P = 0.012) in UDCA-treated subjects (101.0 ± 7.2 mg/ml/120 min) compared with controls (132.5 ± 7.2 mg/ml/120 min.). Percent micellar cholesterol was increased in UDCA-treated versus controls after meal ingestion. No changes were found in cholesterol absorption, FSR, or LDL receptor mRNA with UDCA treatment compared with controls. Thus, despite marked enrichment in luminal bile with UDCA and decreased cholesterol solubilization, no differences in cholesterol absorption or metabolism are found when diet and genetic differences in absorption are carefully controlled. Cholesterol metabolism plays a pivotal role in the development of atherosclerosis. In mammals, relatively constant plasma cholesterol concentrations are regulated by several mechanisms, including intestinal cholesterol absorption, rates of cholesterol synthesis, LDL receptor activity, secretion of cholesterol into bile, and conversion of cholesterol into bile acids. In most nonhuman primates and humans, plasma cholesterol concentrations respond variably to challenges with dietary cholesterol, which has stimulated further investigations into the mechanisms of plasma cholesterol concentration regulation. Though it may have a tremendous impact upon plasma cholesterol levels, cholesterol absorption is the most understudied of the factors that potentially regulate circulating cholesterol levels, as the average North American woman and man consume 240 mg to 360 mg cholesterol per day, respectively, mostly as free cholesterol (1Dietschy 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: 1637-1659Google Scholar, 2Grundy S.M. Absorption and metabolism of dietary cholesterol.Annu. Rev. Nutr. 1983; 3: 71-96Google Scholar). Thus, a significant difference in the amount of cholesterol entering the body can occur based upon the extent of cholesterol absorbed by the intestine. The extent of cholesterol absorbed by the intestine is governed by intraluminal and mucosal events. The major intraluminal events essential to intestinal fat and sterol absorption include digestion and solubilization of lipolytic products. For the small proportion of dietary cholesterol present in esterified forms (8–19%) (2Grundy S.M. Absorption and metabolism of dietary cholesterol.Annu. Rev. Nutr. 1983; 3: 71-96Google Scholar), pancreatic cholesterol esterase hydrolyzes the esters, producing free cholesterol and fatty acid. Dietary and biliary cholesterol is emulsified with triglycerides and other undigested lipids in oily droplets. Intraluminal fat digestion is affected by several lipolytic enzymes, thereby generating a multilamellar crystalline phase. The liquid crystalline phase, comprised of vesicles, provides substrates for micelles. The micelles and/or monomeric cholesterol crosses the unstirred water layer followed by movement of monomeric cholesterol across the brush border membrane either through passive diffusion or by a carrier-mediated mechanism (3Hauser H. Dyer J.H. Nandy A. Vega M.A. Werder M. Bieliauskaite E. Weber F.E. Compassi S. Gemperli A. Boffelli D. Wehrli E. Schulthess G. Phillips M.C. Identification of a receptor mediating absorption of dietary cholesterol in the intestine.Biochemistry. 1998; 37: 17843-17850Google Scholar, 4Hernandez M. Montenegro J. Steiner M. Kim D. Sparrow C. Detmers P.A. Wright S.D. Chao Y-S. Intestinal absorption of cholesterol is mediated by a saturable inhibitable transporter.Biochim. Biophys. Acta. 2000; 1486: 232-242Google Scholar, 5Yu L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. Overexpression of ABCG5 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol.J. Clin. Invest. 2002; 110: 671-680Google Scholar). Thus, the ability to form micelles, as occurs in vitro with bile acids of different compositions, could have a dramatic effect on cholesterol absorption. It has been suggested for years that the amount of exogenous cholesterol that enters the body plays a major role in the formation of hypercholesterolemia. For example, dietary cholesterol directly correlates with plasma total and LDL cholesterol concentrations and can impact upon the development of atherosclerosis (6Gylling H. Miettinen T.A. Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men and different apoE phenotypes.J. Lipid Res. 1992; 33: 1361-1371Google Scholar). Additionally, the variations that occur in plasma cholesterol levels within various populations have been suggested to occur at the level of cholesterol absorption (7Katan M.B. Beynen A.C. DeVries J.H.M. Nobels A. Existence of consistent hypo- and hyper responders to dietary cholesterol in man.Am. J. Epidemiol. 1986; 123: 221-234Google Scholar, 8Katan M.B. Beynen A.C. Characteristics of human hypo- and hyper responders to dietary cholesterol.Am. J. Epidemiol. 1987; 125: 387-399Google Scholar, 9Kesaniemi Y.A. Miettinen T.A. Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population.Eur. J. Clin. Invest. 1987; 17: 391-395Google Scholar, 10Safonova I.G. Sviridov D.D. Roytman A. Rytikov F.M. Dolgov V.V. Nano J-L. Rampal P. Repin V.S. Cholesterol uptake in the human intestine. Hypo- and hyper responsiveness.Biochim. Biophys. Acta. 1993; 1166: 313-316Google Scholar). Most convincing, however, is that when cholesterol absorption is directly inhibited, plasma cholesterol concentrations decrease (11Harwood Jr., H.J. Chandler C.E. Pellarin L.D. Bangerter F.W. Wilkins R.W. Long C.A. Cosgrove P.G. Malinow M.R. Marzetta C.A. Pettini J.L. Savoy Y.E. Mayne J.T. Pharmacologic consequences of cholesterol absorption inhibition: alteration in cholesterol metabolism and reduction in plasma cholesterol concentration induced by the synthetic saponin β-tigogenin cellobioside (CP-88818; tiqueside).J. Lipid Res. 1993; 34: 377-395Google Scholar). The purpose of the current investigation was to examine the role of intraluminal bile acid composition on intraluminal micelle formation, and ultimately cholesterol absorption and synthesis and circulating levels. To accomplish this goal, adults were fed diets with or without supplementation with ursodeoxycholic acid (UDCA), a bile acid whose micelle formation is less efficient than the primary bile acids in vitro (12Roda A. Hofmann A.F. Mysels K.J. The influence of bile salt structure on self-association in aqueous solutions.J. Biol. Chem. 1983; 258: 6362-6370Google Scholar). We hypothesized that quantitative and qualitative alterations in intraluminal bile acid composition would influence micelle formation and, therefore, the efficiency of cholesterol absorption, which in turn would vary inversely with cholesterol fractional synthetic rate (FSR), HMG-CoA reductase, and LDL-receptor mRNA levels. Subjects were healthy adult Caucasian males and females, ages 24–36, recruited by advertisement and screened for any evidence of cardiovascular, pulmonary, renal, or gastrointestinal, hepatobiliary disease, or soy allergy. Subjects were excluded with diabetes mellitus, chronic usage of any medication, including oral contraceptives, and plasma total and LDL cholesterol exceeding 200 mg/dl and 120 mg/dl, respectively. Subjects were screened for apolipoprotein (apo) A-IV and apoE genotypes. Only subjects with apoA-IV 1/1 and apoE 3/3 genotypes were included. Females of childbearing age could not be to be and could not be during the of this The of the of and the the that and a of the study, subjects a form the To be to subjects to at on a that of the The a diet and was for total fat and upon intake the diet and levels, the total to and diet were on a The diets were to mg with as fat with a of Subjects diets and by the subjects to the or to diets that been after and bile acid were while on the study, subjects were in without a to maintenance of subjects to the after and for plasma total, HDL, and LDL cholesterol, and and HMG-CoA and LDL-receptor mRNA levels. a randomized crossover subjects either UDCA mg/kg/day in a or of bile acid or no supplement was a on the diet subjects were after a at the was for total, and cholesterol, and and for mRNA levels and LDL A was with with the at the of was by for 15 Subjects then a meal M.C. of dietary and biliary during intestinal digestion and absorption. and of luminal lipids during fat digestion in healthy adult human Scholar, M. P. C. M. M. J. J. D. of and of dietary lipids in the human J. Scholar, L. D.D. H. P. of micelles and within healthy of cholesterol after a Lipid Res. 2002; Scholar). was in 15 for and then of collection 15 were for for of cholesterol and The of the was to the and the were as L. D.D. H. P. of micelles and within healthy of cholesterol after a Lipid Res. 2002; Scholar). days subjects to the that oral and of cholesterol were given and at and at and cholesterol was was for cholesterol Subjects were given oral and the was at the as the on the dietary subjects in the of the after a of at the of events was as for the phase of the total cholesterol, LDL cholesterol, and concentrations were by the of Lipid collection of samples the study, and and were to the M.C. of dietary and biliary during intestinal digestion and absorption. and of luminal lipids during fat digestion in healthy adult human Scholar). of the composition was M.C. of dietary and biliary during intestinal digestion and absorption. and of luminal lipids during fat digestion in healthy adult human Scholar, M. P. C. M. M. J. J. D. of and of dietary lipids in the human J. Scholar, L. D.D. H. P. of micelles and within healthy of cholesterol after a Lipid Res. 2002; Scholar). were into the and by were by the of J. M. A for the and of total lipids animal Biol. Chem. Scholar), and were the L. to of with qualitative and quantitative variations of Biol. Scholar). Cholesterol was in and by as and bile acids were by as A. C. P. C. C. A. of free and bile acids by liquid with Lipid Res. 1992; 33: Scholar, S.D. J.M. and of the plasma for the of intestinal cholesterol absorption in the Lipid Res. Scholar). The bile acid concentration was L. D.D. H. P. of micelles and within healthy of cholesterol after a Lipid Res. 2002; and to a to the micelles and including vesicles, by were on a comprised of Cholesterol was in either or by were defined as that as the as HDL, and were Cholesterol absorption was by the of as by Jr., R.E. J. C. of cholesterol absorption in with stable Lipid Res. 1993; 34: Scholar, A for the of cholesterol absorption in Biol. Scholar). of cholesterol was in and into was given mg that was in at 15 and to The was with a of 240 of and 240 of samples at and were and plasma at cholesterol was to cholesterol and cholesterol The of free cholesterol were by The of free cholesterol were by a with The average and of and free cholesterol to = samples were to the cholesterol absorption the of cholesterol to cholesterol as by Jr., R.E. J. C. of cholesterol absorption in with stable Lipid Res. 1993; 34: Scholar). cholesterol synthesis based on was and in by and D. as in the of on the uptake of into with to fat and cholesterol Biol. Chem. Scholar), and by and of in cholesterol synthesis a for the and isotopic of cholesterol.J. Lipid Res. and of water for of cholesterol synthesis in J. Scholar, P. C.A. cholesterol synthesis and 1993; Scholar). is based on the that the rate of of the stable into membrane cholesterol as of cholesterol synthesis rates J.M. Spady D.K. of rates of cholesterol synthesis Lipid Res. Scholar, of sterol for of human cholesterol Lipid Res. 1998; Scholar). The was the was and 15 samples of of and for body water and cholesterol The was then with per body water body by and with a subjects were to consume water a for enrichment was were at the as on were to the this on and the cholesterol on was as by enrichment on Cholesterol was as the rate of of body water into membrane free cholesterol the and at the of water and water and of cholesterol formation rates H. The of the cholesterol of human Clin. Invest. Scholar, J.M. of rates of cholesterol synthesis in in the liver and of the Lipid Res. Scholar). enrichment was in cholesterol and plasma To plasma cholesterol total lipids were and the Cholesterol fractional synthesis rate (FSR) was to the cholesterol enrichment to the plasma water enrichment after for the free cholesterol The that of the cholesterol that is in and was as C.A. cholesterol synthesis and 1993; Scholar). was to of was to with was by to a A was to of with to of that was within of mRNA by the Scholar). the as for the therefore, no efficiency differences A was that in that by mRNA were on a and with and was with a The of the for mRNA and the for was the for the of the of the for K.E. and Scholar). of the were by the and the it was that the amount of to the concentration of the without and without The were human LDL and and human and was to in the was as by and of human apolipoprotein by and with Lipid Res. Scholar). was as by and of human apolipoprotein of and of a that a Lipid Res. Scholar). was to on The the form for and forms were to the A. for were to the on and in the at the of were and qualitative alterations in intraluminal bile acid composition influence the efficiency of cholesterol absorption. To this the the effect of of or the of with treatment or no a significant effect on any were with the For the of micelles and at the various the was a with as the were in the treatment or no and of treatment with UDCA or no treatment. of the of with the could not be and were to be For other the was a with as the effect and treatment supplementation or no as the In the of with this difference is to that were for composition within the for the H. and 232-242Google Scholar, R.E. design with Scholar, J. for the Scholar). for changes were by UDCA-treated were to examine changes in are as ± the to the were at of of the impact of bile acid composition on cholesterol absorption that the effect of bile acid composition on absorption with at and M. P. Cholesterol absorption during bile acid Scholar, H. of different bile acids on intestinal cholesterol absorption in Scholar). of the the of the differences in absorption. suggested that a difference in absorption would be upon the to a of effect of and a of adults men and age 24–36 years the the subjects with a on the diet versus on diet Subjects average of while and while cholesterol and and fat was during subjects were with the diet with diet with UDCA was with subjects or of the mg No subjects or with bile acid and no No could be on when was for the liquid meal is for The of 12 of UDCA at a of 15 mg/kg/day in in significant (P < 0.0001) enrichment of the biliary bile acids with intraluminal bile acid in the were ± in UDCA-treated compared with ± during the With the meal UDCA enrichment of bile in the for 2.2 ± 2.6% significantly different of luminal bile while with UDCA treatment, UDCA for 40.6 ± With treatment with the bile acid composition of the primary and bile acids was bile acid acid for ± of biliary bile while on UDCA it to ± without acid for ± which to ± with UDCA treatment. acid enrichment relatively constant with ± without supplementation versus ± with UDCA treatment. No acid in bile was with either total, HDL, and LDL cholesterol, and concentrations not with UDCA treatment. days of diet the plasma total cholesterol concentration was ± 2.2 mg/dl, cholesterol was ± mg/dl, LDL cholesterol was ± mg/dl, and plasma triglycerides were ± days of diet UDCA at a of 15 was no = in the plasma cholesterol ± 2.2 cholesterol ± plasma LDL cholesterol ± or plasma ± In to the intraluminal cholesterol solubilized in the aqueous phase during the entire collection was decreased significantly (P = 0.012) with UDCA treatment (101.0 ± 7.2 mg/ml/120 min) compared with diet (132.5 ± 7.2 mg/ml/120 min) were no differences in the the for The micellar cholesterol was during UDCA treatment diet compared with diet at the was a for of cholesterol in micelles in the UDCA-treated collection were the micellar cholesterol was ± and cholesterol ± during the UDCA treatment (P = A of the cholesterol was in the as vesicles, with a as of cholesterol micelles and including vesicles, of subjects on no bile acid supplementation or UDCA treatment. samples were as in and and based on The amount of cholesterol in was or by Cholesterol concentrations in are for subjects no bile acid or UDCA significantly different at the are as ± Cholesterol absorption by the stable of cholesterol was unchanged with UDCA treatment With diet cholesterol absorption was ± compared with ± when subjects were with diet With no changes in cholesterol absorption, it was not that cholesterol were unchanged by UDCA treatment The on diet UDCA was ± while with diet the was ± for other of cholesterol LDL receptor and HMG-CoA mRNA were unchanged by UDCA treatment. LDL receptor mRNA was ± in UDCA subjects compared with ± in subjects given diet HMG-CoA mRNA was ± while UDCA and and ± on diet fractional synthetic rates for fed diets for days with UDCA or no bile acids. Subjects and then were and as in and were changes in various with treatment with no significant were found the in cholesterol absorption in subjects and the cholesterol or cholesterol FSR, LDL-receptor or HMG-CoA A was found the in and in LDL receptor mRNA with UDCA treatment = < was a the in mRNA HMG-CoA and < The of this investigation was to the effect of differences in bile acid composition on intraluminal cholesterol and lipolytic solubilization, intestinal cholesterol absorption, cholesterol synthesis, and LDL receptor the in a of to the of supplementation with and acid on cholesterol absorption and metabolism in healthy of the lipolytic of fat cholesterol, and by bile is essential for absorption are in aqueous and are upon the of bile acids for in the intraluminal of bile in intestinal absorption of cholesterol.J. Biol. Chem. Scholar, L. Jr., Jr., H. of bile in cholesterol Biol. Scholar, H. J.M. The mechanism bile acid micelles the rate of fatty acid and cholesterol uptake into the intestinal mucosal Clin. Invest. Scholar). The efficiency of sterol absorption to be related to the of the bile salt intraluminal bile salt concentrations the micellar cholesterol absorption is The of qualitative differences in bile acid composition have been Most of have bile in vitro or in with and qualitative differences in dietary fat composition or cholesterol may alter to luminal bile acid and to that are to Dietary of cholesterol Scholar). have been and no has carefully the effect of a of bile acids on cholesterol absorption with a in including the of absorption may be related to design diet fat and cholesterol and methods. In the current study, found no differences in cholesterol absorption the in a of healthy adults were carefully screened for disease, and apoE and apoA-IV genotypes of on cholesterol absorption (6Gylling H. Miettinen T.A. Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men and different apoE phenotypes.J. Lipid Res. 1992; 33: 1361-1371Google Scholar, T.A. H. H. A. Cholesterol absorption, and synthesis related to LDL during varying fat intake in men with different 1992; Scholar, J. to a diet in subjects for the apolipoprotein J. Scholar, P. J.M. J. J.T. A-IV plasma LDL cholesterol and plasma concentrations after of a carefully sterol absorption with UDCA treatment have are in with of and found no in cholesterol absorption in UDCA-treated adults with to diets mg for days J.L. of bile acids on cholesterol absorption in 1983; Scholar), and with found no in cholesterol absorption in subjects given diets mg G. J.M. Cholesterol absorption and sterol in subjects dietary or ursodeoxycholic Scholar), not for diet as as the present In to found that cholesterol absorption to while subjects were on UDCA a diet mg M. P. Cholesterol absorption during bile acid Scholar). found cholesterol absorption on in subjects with without any dietary H. of different bile acids on intestinal cholesterol absorption in Scholar). and found in cholesterol absorption in males a liquid fat with a of found that absorption was at compared with on UDCA and on acid S.M. of and on bile acid synthesis and cholesterol Scholar). and found cholesterol absorption to in subjects with on no dietary A. of ursodeoxycholic acid on biliary and on cholesterol absorption during and in subjects with cholesterol Scholar). The for the the and may be related to differences in The of and the isotopic to absorption, while the sterol The other and In in the in which diet was carefully subjects of cholesterol to was by The effect of dietary cholesterol on the ability of UDCA to plasma cholesterol concentrations is men and most subjects in were is may be differences in cholesterol absorption in humans, as in P. UDCA is to form micelles less than the primary bile acids (12Roda A. Hofmann A.F. Mysels K.J. The influence of bile salt structure on self-association in aqueous solutions.J. Biol. Chem. 1983; 258: 6362-6370Google Scholar). It was that enrichment of the with UDCA would to cholesterol absorption, to cholesterol the in vitro cholesterol solubilized in the aqueous phase of subjects fed UDCA was significantly compared with the without bile acid the of cholesterol in the were no differences in cholesterol absorption. The of cholesterol in micellar phase was after a liquid meal when subjects were with UDCA and diet versus with diet It is that the micellar cholesterol in the UDCA treatment phase may have been by the cholesterol, thereby to no effect of UDCA on intraluminal solubilization of dietary cholesterol and no impact on cholesterol absorption. In solubilization in the aqueous phase was during treatment In that UDCA not have a major impact upon intraluminal events when with other bile acids and or in the that was no significant in cholesterol absorption with UDCA treatment, it is not that the for cholesterol, or LDL-receptor and HMG-CoA mRNA were not directly LDL receptor and HMG-CoA mRNA levels, have the and P.A. density lipoprotein receptor and A in human is regulated and in human Clin. Invest. Scholar). would that would be a mRNA levels and cholesterol absorption L. Dietary cholesterol human cholesterol synthesis by and acid Biol. Scholar, D. S.M. E. of the lipoprotein receptor by dietary cholesterol.Am. J. Clin. Nutr. Scholar, M. of diet to LDL cholesterol, cholesterol, and plasma total cholesterol and triglycerides in Scholar), it is to that without changes in absorption, other not thereby as for the of in plasma cholesterol concentration not be in the in plasma cholesterol concentrations in with the plasma cholesterol concentrations Hofmann A.F. acid in the treatment of cholesterol Scholar, R.E. C. E. Cholesterol effect of ursodeoxycholic acid in with primary biliary 1993; 17: Scholar). in and adults have The reduction has been in with plasma cholesterol with significant Hofmann A.F. acid in the treatment of cholesterol Scholar, R.E. C. E. Cholesterol effect of ursodeoxycholic acid in with primary biliary 1993; 17: Scholar). have to a major effect of biliary enrichment with UDCA on cholesterol absorption and synthesis, plasma and LDL receptor mRNA in a healthy intraluminal solubilization of cholesterol was when bile was enriched with impact on cholesterol absorption and metabolism are to the of UDCA on cholesterol solubilization and the of micellar and cholesterol on absorption in animal the human are to the of biliary enrichment with and acid on cholesterol absorption and

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