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J. Biol. Chem., Vol. 277, Issue 42, 39243-39250, October 18, 2002
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(PPAR) in HEK293
Cells*
§,§,,
From the Fatty acids bind to and regulate the activity of
peroxisome proliferator-activated (PPAR) and liver X receptors (LXR).
However, the role lipid metabolism plays in the control of
intracellular fatty acid ligands is poorly understood. We have
identified two strains of HEK293 cells that display differences in
fatty acid regulation of nuclear receptors. Using full-length and
Gal4-LBD chimeric receptors in functional assays, 20:4,n6 induced
PPAR Departments of Physiology, Biochemistry, and
Molecular Biology, Michigan State University, East Lansing, Michigan
48824 and the ¶ Department of Pharmacology and Howard Hughes
Medical Institute, University of Texas, Southwestern Medical Center,
Dallas, Texas 75390-9050
activity ~2.2-fold and suppressed LXR activity by 80%
(ED50 ~25-50 µM) in HEK293-E (early
passage) cells but had no effect on PPAR or LXR receptor activity
in HEK293-L (late passage) cells. LXR
was insensitive to fatty acid
regulation in both HEK293 strains. Metabolic labeling studies using
[14C]20:4,n6 (at 100 µM) indicated that the
uptake of 20:4,n6 and its assimilation into triacylglycerol,
diacylglycerol, and polar lipids revealed no difference between the two
strains. Such treatment increased total cellular 20:4,n6 (~11-fold)
and its elongation product, 22:4,n6 (~3.6-fold), within 6 h.
Non-esterified 20:4,n6 and 22:4,n6 represented 
3% of the total
cellular 20:4,n6 and 22:4,n6. In HEK293-E cells, non-esterified 20:4,n6
and 22:4,n6 increased 8- and 18-fold, respectively, by 6 h and was
sustained at that level for 24 h. In HEK293-L cells,
non-esterified 20:4,n6 also increased (5-fold) at 6 h but fell by
70% within 24 h. In contrast to HEK293-E cells, non-esterified
22:4,n6 did not accumulate in HEK293-L cells. Functional assays showed
that 22:4,n6 was ~2-fold more effective than 20:4,n6 at inhibiting
oxysterol-induced LXR activity in HEK293-E cells, but had no effect
on LXR activity in HEK293-L cells. Taken together, these findings
demonstrate that the rate of assimilation of exogenously added fatty
acids and their metabolites into complex lipids plays an important role in regulating PPAR and LXR activity.
To whom correspondence should be addressed: Dept. of
Physiology, 3165 Biomedical and Physical Science Bldg., Michigan State University, East Lansing, MI 48824. Tel.: 517-355-6475, Ext. 1133; Fax:
517-355-5125; E-mail: Jump@msu.edu.
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