Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse.
We explored the influence of the hydrophilic-hydrophobic balance of a series of natural bile acids on cholesterol absorption in the mouse. Male C57L/J mice were fed standard chow or chow supplemented with 0.5% cholic; chenodeoxycholic; deoxycholic; dehydrocholic; hyocholic; hyodeoxycholic; alpha-, beta-, or omega-muricholic; ursocholic; or ursodeoxycholic acids for 7 days. Biliary bile salts were measured by reverse-phase HPLC, and hydrophobicity indices were estimated by Heuman's method. Cholesterol absorption efficiency was determined by a plasma dual-isotope ratio method. In mice fed chow, natural proportions of tauro-beta-muricholate (42 +/- 6%) and taurocholate (50 +/- 7%) with a hydrophobicity index of -0.35 +/- 0.04 produced cholesterol absorption of 37 +/- 5%. Because bacterial and especially hepatic biotransformations of specific bile acids occurred, hydrophobicity indices of the resultant bile salt pools differed from fed bile acids. We observed a significant positive correlation between hydrophobicity indices of the bile salt pool and percent cholesterol absorption. The principal mechanism whereby hydrophilic bile acids inhibit cholesterol absorption appears to be diminution of intraluminal micellar cholesterol solubilization. Gene expression of intestinal sterol efflux transporters Abcg5 and Abcg8 was upregulated by feeding cholic acid but not by hydrophilic beta-muricholic acid nor by hydrophobic deoxycholic acid. We conclude that the hydrophobicity of the bile salt pool predicts the effects of individual fed bile acids on intestinal cholesterol absorption. Natural alpha- and beta-muricholic acids are the most powerful inhibitors of cholesterol absorption in mice and might act as potent cholesterol-lowering agents for prevention of cholesterol deposition diseases in humans.
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. dqwang@caregroup.harvard.edu
David Q-H
DQ
Wang
Susumu
S
Tazuma
David E
DE
Cohen
Martin C
MC
Carey
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology*; D002769:Cholelithiasis / Q000209:etiology*; D002784:Cholesterol / Q000378:metabolism*; D019587:Dietary Supplements; D004198:Disease Susceptibility; D005772:Gastrointestinal Transit; D015870:Gene Expression; D057927:Hydrophobic and Hydrophilic Interactions; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D008074:Lipoproteins; D002784:Cholesterol