Biliary sterol secretion is required for functional in vivo reverse cholesterol transport in mice.
OBJECTIVE
High-density lipoproteins (HDLs) protect against atherosclerotic cardiovascular disease, mainly by promoting reverse cholesterol transport (RCT). Biliary sterol secretion supposedly represents the final step in RCT, but the relevance of this pathway has not been explored. We tested the dependency of RCT on functional biliary sterol secretion.


METHODS
Macrophage-to-feces RCT was studied in mice with abolished (bile duct ligation) or decreased biliary sterol secretion (adenosine triphosphate binding cassette transporter B4 (Abcb4)-/- mice, with and without administration of a liver X receptor [LXR] agonist) after intraperitoneal injection of (3)H-cholesterol-loaded primary macrophage foam cells from mice. Fecal tracer excretion and also fecal mass sterol excretion were measured. Metabolism and tissue uptake of HDL cholesteryl ester was assessed with HDL kinetic studies.


RESULTS
Bile-duct ligation completely abolished RCT from (3)H-cholesterol-loaded macrophages to feces (P < .001). In Abcb4-/- mice lacking biliary cholesterol secretion, RCT was decreased markedly; fecal (3)H-tracer excretion was almost absent within neutral sterols (P < .001) and reduced within bile acids (P < .05). LXR activation stimulated RCT in wild-type (5.5-fold; P < .001) but not Abcb4-/- mice, whereas mass fecal sterol excretion increased similarly in both models (P < .05). Kinetic studies revealed minimal uptake of HDL cholesteryl ester by the intestine, which decreased on LXR activation (P < .05).


CONCLUSIONS
Functional RCT depends on biliary sterol secretion; there is no compensatory increase in RCT via bile acids. The stimulating effect of LXR agonists on RCT requires biliary cholesterol secretion. These results have implications for therapies against atherosclerotic cardiovascular disease targeting the RCT pathway.
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Niels
N
Nijstad
Thomas
T
Gautier
François
F
Briand
Daniel J
DJ
Rader
Uwe J F
UJ
Tietge
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D003135:Common Bile Duct / Q000378:metabolism* / Q000601:surgery; D005243:Feces / Q000737:chemistry; D005487:Foam Cells / Q000378:metabolism* / Q000637:transplantation; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D008026:Ligation; D008075:Lipoproteins, HDL / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D002784:Cholesterol; D002788:Cholesterol Esters; D006845:Hydrocarbons, Fluorinated; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C059714:HDL cholesteryl ester; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides