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Papers In Press, published online ahead of print August 2, 2002
J. Biol. Chem, 10.1074/jbc.M206170200
Submitted on June 20, 2002
Revised on August 2, 2002
Accepted on August 2, 2002
Department of Physiology, Michigan State University, East Lansing, MI 48824
Corresponding Author: Jump{at}msu.edu
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 PPARa activity ~2.2-fold and suppressed LXRa activity by 80% (ED50 ~ 25-50 µM) in HEK293-E (early passage) cells, but had no effect on PPARa or LXRa receptor activity in HEK293-L (late passage) cells. LXRß was insensitive to fatty acid regulation in both HEK293 strains. Metabolic labeling studies using 14C-20:4,n6 (at 100 mM) 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 hrs. 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 hrs and was sustained at that level for 24 hrs. In HEK293-L cells, non-esterified 20:4,n6 also increased (5-fold) at 6 hr, but fell by 70% within 24 hrs. 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 LXRa activity in HEK293-E cells, but had no effect on LXRa 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 PPARa and LXRa activity.
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