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Journal of Lipid Research, Vol 35, 1661-1673, Copyright © 1994 by Lipid Research, Inc.
LA Woollett, CM Daumerie and JM Dietschy
The concentration of cholesterol carried in low density lipoproteins
(LDL-C) is primarily determined by the rate at which LDL-C is produced (Jt)
and the rate at which the liver takes up this particle through
receptor-dependent transport (Jm). The accumulation of specific dietary
fatty acids in the liver profoundly alters these kinetic parameters and
will either increase hepatic receptor activity or further suppress Jm,
depending upon the particular fatty acid that enriches the various lipid
pools. This study tests the thesis that the cellular effects of each fatty
acid are determined by the ability of that lipid to act as an effective
substrate for cholesteryl ester formation by examining the metabolic
effects of either cis-9-octadecenoic acid (18:1(9c)), the preferred
substrate for esterification, or trans-9-octadecenoic acid (18:1(9t)), a
poor substrate for this reaction. When fed to hamsters for 30 days, the
steady-state concentration of cholesteryl esters was markedly increased by
the 18:1(9c), as compared to the 18:1(9t), compound. In animals receiving
the 18:1(9c) fatty acid, hepatic receptor activity was significantly
increased, LDL-C production was suppressed, and the steady-state LDL-C
concentration was reduced. In contrast, the 18:1(9t) fatty acid did not
significantly alter Jm, Jt, or the plasma LDL-C level from those values
found in the control animals fed an isocaloric amount of a biologically
neutral fatty acid, octanoic acid. Despite these different effects on the
parameters of LDL metabolism, neither the cis nor trans fatty acid altered
net cholesterol delivery to the liver from de novo sterol synthesis in any
tissue in the body or from uptake of dietary cholesterol across the
intestine. Therefore, these studies provide strong support for the thesis
that fatty acids exert regulatory effects on hepatic LDL receptor activity
by altering the distribution of cholesterol in the hepatocyte between a
putative regulatory pool and the inert pool of cholesteryl esters. The
direction and magnitude of the effects of specific fatty acids on
receptor-dependent LDL transport appear to relate directly to the capacity
of specific fatty acids to either promote or inhibit cholesteryl ester
formation.
ARTICLES
Trans-9-octadecenoic acid is biologically neutral and does not regulate the low density lipoprotein receptor as the cis isomer does in the hamster
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8887.
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