Receptor-mediated uptake of low density lipoprotein stimulates bile acid synthesis by cultured rat hepatocytes.
The cellular mechanisms responsible for the lipoprotein-mediated stimulation of bile acid synthesis in cultured rat hepatocytes were investigated. Adding 280 micrograms/ml of cholesterol in the form of human or rat low density lipoprotein (LDL) to the culture medium increased bile acid synthesis by 1.8- and 1.6-fold, respectively. As a result of the uptake of LDL, the synthesis of [14C]cholesterol from [2-14C]acetate was decreased and cellular cholesteryl ester mass was increased. Further studies demonstrated that rat apoE-free LDL and apoE-rich high density lipoprotein (HDL) both stimulated bile acid synthesis 1.5-fold, as well as inhibited the formation of [14C]cholesterol from [2-14C]acetate. Reductive methylation of LDL blocked the inhibition of cholesterol synthesis, as well as the stimulation of bile acid synthesis, suggesting that these processes require receptor-mediated uptake. To identify the receptors responsible, competitive binding studies using 125I-labeled apoE-free LDL and 125I-labeled apoE-rich HDL were performed. Both apoE-free LDL and apoE-rich HDL displayed an equal ability to compete for binding of the other, suggesting that a receptor or a group of receptors that recognizes both apolipoproteins is involved. Additional studies show that hepatocytes from cholestyramine-treated rats displayed 2.2- and 3.4-fold increases in the binding of apoE-free LDL and apoE-rich HDL, respectively. These data show for the first time that receptor-mediated uptake of LDL by the liver is intimately linked to processes activating bile acid synthesis.
Junker
L H
LH
Cell and Molecular Biology Unit, University of Colorado Health Sciences Center, Denver 80262.
Davis
R A
RA
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D002792:Cholestyramine Resin / Q000494:pharmacology; D006801:Humans; D007457:Iodine Radioisotopes; D008055:Lipids / Q000096:biosynthesis; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D011973:Receptors, LDL / Q000502:physiology*
D001647:Bile Acids and Salts; D007457:Iodine Radioisotopes; D008055:Lipids; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002792:Cholestyramine Resin; D002784:Cholesterol