Studies on the mechanism of the ursodeoxycholic acid-induced increase in hepatic low-density lipoprotein binding.
Previously, we have shown, in golden Syrian hamsters, that chronic feeding of ursodeoxycholic acid (UDCA), in contrast to that of its 7 alpha-epimer, chenodeoxycholic acid (CDCA), produced a significant increment in hepatic low-density lipoprotein (LDL) uptake, despite similar suppression of bile acid synthesis by both bile acids. Evidence for a direct effect of this bile acid on hepatic LDL metabolism was shown in vitro, with isolated hamster hepatocytes, suggesting that this effect was unique to UDCA and specific for receptor-mediated LDL catabolism. The aim of the present study was to define the cellular mechanism(s) associated with this phenomenon, using male golden Syrian hamsters. Regardless of chronic exposure of the liver to either UDCA or CDCA, acute incubation with UDCA consistently resulted in an increase of LDL binding to isolated hepatocytes by 15 to 40%. Furthermore, chronic treatment with either UDCA or CDCA did not result in alterations in lipoprotein particle composition. Likewise, incubation of hepatocytes with UDCA was not associated with a change of the membrane lipid composition. In isolated liver membrane fractions, UDCA increased both the maximum number of LDL binding sites and the affinity constant for LDL by around 35%, suggesting an interaction of UDCA with the LDL receptor, at the plasma membrane level, independent of an effect on receptor cycling. The results of the studies support a role for UDCA in the recruitment of cryptic LDL receptors from a cellular membrane pool, possibly due to the unique localization of UDCA in the plasma membrane lipid bilayer.
Bouscarel
B
B
Department of Medicine, George Washington University Medical Center, Washington, DC 20037, USA.
Ceryak
S
S
Robins
S J
SJ
Fromm
H
H
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D007457:Iodine Radioisotopes; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008563:Membrane Lipids / Q000032:analysis; D008647:Mesocricetus; D011973:Receptors, LDL / Q000502:physiology; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D001647:Bile Acids and Salts; D007457:Iodine Radioisotopes; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D008563:Membrane Lipids; D011973:Receptors, LDL; D014580:Ursodeoxycholic Acid