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J Biol Chem, Vol. 274, Issue 7, 3970-3977, February 12, 1999
From the Department of Biochemistry, Molecular Biology and
Biophysics, University of Minnesota, St.
Paul, Minnesota 55108
Fatty acid transport protein (FATP),
a plasma membrane protein implicated in controlling adipocyte
transmembrane fatty acid flux, is up-regulated as a consequence of
adipocyte differentiation and down-regulated by insulin. Based upon the
sequence of the FATP gene upstream region (Hui, T. Y., Frohnert,
B. I., Smith, A. J., Schaffer, J. A., and Bernlohr,
D. A. (1998) J. Biol. Chem. 273, 27420-27429) a
putative peroxisome proliferator-activated receptor response element
(PPRE) is present from 
458 to 474. To determine whether the FATP
PPRE was functional, and responded to lipid activators, transient
transfection of FATP-luciferase reporter constructs into CV-1 and
3T3-L1 cells was carried out. In CV-1 cells, FATP-luciferase activity
was up-regulated 4- and 5.5-fold, respectively, by PPAR
and PPAR
in the presence of their respective activators in a
PPRE-dependent mechanism. PPAR
, however, was unable to
mediate transcriptional activation under any condition. In 3T3-L1
cells, the PPRE conferred a small but significant increase in
expression in preadipocytes, as well as a more robust up-regulation of
FATP expression in adipocytes. Furthermore, the PPRE conferred the
ability for luciferase expression to be up-regulated by activators of
both PPAR and retinoid X receptor (RXR) in a synergistic
manner. PPAR and PPAR activators did not up-regulate FATP
expression in 3T3-L1 adipocytes, however, suggesting that these two
subtypes do not play a significant role in
differentiation-dependent activation in fat cells.
Electromobility shift assays showed that all three PPAR subtypes were
able to bind specifically to the PPRE as heterodimers with RXR.
Nuclear extracts from 3T3-L1 adipocytes also showed a specific
gel-shift complex with the FATP PPRE. To correlate the expression of
FATP to its physiological function, treatment of 3T3-L1 adipocytes with
PPAR and RXR activators resulted in an increased uptake of
oleate. Moreover, linoleic acid, a physiological ligand, up-regulated FATP expression 2-fold in a PPRE-dependent manner. These
results demonstrate that the FATP gene possesses a functional PPRE and is up-regulated by activators of PPAR and PPAR, thereby linking the activity of the protein to the expression of its gene. Moreover, these results have implications for the mechanism by which certain PPAR activators such as the antidiabetic thiazolidinedione drugs affect adipose lipid metabolism.
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