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Studies on the mechanism of the ursodeoxycholic acid-induced increase in hepatic low-density lipoprotein binding

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Lipids

Abstract

Previously, we have shown, in golden Syrian hamsters, that chronic feeding of ursodeoxycholic acid (UDCA), in contrast to that of its 7α-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 shownin 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.

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Abbreviations

CDCA:

chenodeoxycholic acid

FC:

free cholesterol

GUDCA:

glycine conjugate of UDCA

HDL:

high-density lipoprotein

IDL:

intermediate-density lipoprotein

LDL:

low-density lipoprotein

PAGE:

polyacrylamide gel electrophoresis

PC:

phosphatidylcholine

PL:

phospholipid

TG:

triglyceride

TUDCA:

taurine conjugate of UDCA

UDCA:

ursodeoxycholic acid

VLDL:

very low density lipoprotein

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Authors and Affiliations

  1. Division of Gastroenterology and Nutrition, Department of Medicine, The George Washington University Medical Center, 2300 I St. N.W., 523 Ross Hall, 20037, Washington, DC

    Bernard Bouscarel, Susan Caryak & Hans Fromm

  2. Lipid Metabolism Laboratory and Department of Medicine, Veterans Administration Medical Center, 02130, Boston, Massachusetts

    Sander J. Robins

Authors
  1. Bernard Bouscarel
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  2. Susan Caryak
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  3. Sander J. Robins
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  4. Hans Fromm
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Bouscarel, B., Caryak, S., Robins, S.J. et al. Studies on the mechanism of the ursodeoxycholic acid-induced increase in hepatic low-density lipoprotein binding. Lipids 30, 607–617 (1995). https://doi.org/10.1007/BF02536997

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  • DOI: https://doi.org/10.1007/BF02536997

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