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Vol. 53, Issue 1, 14-22, January 1998
Expression in
Human Liver
Department of Molecular and Experimental Medicine, The Scripps
Research Institute, La Jolla, California 92037 (C.N.A.P., M.-H.H.,
K.J.G., E.F.J.), and
Agouron Institute, La Jolla, California 92037 (J.L.R.)
The peroxisome proliferator activated receptor 
(PPAR) is a member
of the steroid/hormone receptor superfamily that mediates the
peroxisome proliferator-dependent transcriptional activation of genes
encoding several peroxisomal and microsomal enzymes as well as
peroxisome proliferation. Human liver is refractory to the pathological
effects of peroxisome proliferators that are seen in mice. With the use
of RNase protection assays, the ratio of hepatic PPAR mRNA to
-actin mRNA was found to be 1 order of magnitude lower in humans
than that observed in mice. In addition, the isolation of human cDNA
for PPAR that does not encode a functional PPAR because it lacks
exon 6 as a result of alternate RNA splicing suggested that this
process might also diminish the expression of PPAR. RNase protection
analysis of total RNA revealed the presence of splice variants lacking
exon 6 at significant levels in all 10 human liver samples examined.
Supershift analysis using the CYP4A6-Z peroxisome proliferator response
element and antisera specific for PPAR revealed easily detectable
amounts of PPAR DNA binding activity in mouse liver lysates, whereas
human liver lysates contained >10-fold lower amounts of PPAR DNA
binding activity. In contrast to mouse lysates, the amount of PPAR
binding in human lysates was generally less than that of other
unidentified proteins. These results suggest that although humans
retain the coding potential for a functional receptor, the low levels
of PPAR expression in liver may be insufficient to compete
effectively with other proteins that bind to peroxisome proliferator
response elements.
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