Journal of Lipid Research, Vol 30, 1933-1941, Copyright © 1989 by Lipid Research, Inc.
Receptor-mediated uptake of low density lipoprotein stimulates bile acid synthesis by cultured rat hepatocytes
LH Junker and RA Davis
Cell and Molecular Biology Unit, University of Colorado Health Sciences Center, Denver 80262.
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.
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