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Peroxisome proliferator-activated receptors are key regulators in cel! differentiation 151
largely used in the treatment of
hypertriglyceremia and combined
hyperlipidemia.
Nonsteroidal
antiinflammatory drugs (NSAIDs) have also
been shown to bind to ppARa [36]. In
addition, coDjugated linoleic acid isomers,
oxidized phospholipids and a new
thiazolidinedione derivative were recently
shown to be high affinity synthetic ligands for
ppARa [37-39]. ppAR~/() is activated by
polyunsaturated fatty acids [12]. ppARr is
activated by arachidonic acid metabolites
derived from the cyclooxygenase and the
lipoxygenase pathway such as 15-deoxy-~-12,
14 prostaglandin J2 [40, 41] and 15­
hydroxyeicosatetraenoic acid respectively [42,
43]. Other ligands like 9- and 13­
hydroxyoctadecadienoic acid derive from
fatty acids of oxidized LDL [42]. Synthetic
ligands, members of the thiazolidinedione
family are agonists for ppARr [44]. These
drugs are used in treatment of insulin
resistance and type 2 diabetes. In addition,
indomethacin and ibubrofen, two well-known
NSAIDs, function as ligands for ppARr [36].
Phosphorylationldephosphorylation
This process is an important mechanism of
ppAR activation ; it is also necessary for
others transcription factors [21]. However,
ppARa is activated by phosphorylation as
does estrogen receptor for exemple whereas
transactivation of ppARr implicates
dephosphorylation within the AF-I domain.
Rurnan ppARa is phosphorylated at serine 12
and 21 in the AF-l domain by MAPK
pathway [45]. Phosphorylation is insulin
dependent [46] and is modulated by an
unknown inhibitor under the control of Janus
kinase 2/Signal Transducer and Activator of
Transcription 5b (JAK2/STAT5b) himself
regulated by growth hormone stimulation
[47]. Ciprofibrate treatment in rat cells
enhances phosphorylation of ppARa [48].
Unexpectedly, the PPARa phosphorylation
leads to a decrease ofacyl-coA oxidase, a
peroxisomal fatty acid ~-oxydation marker
[48]. In addition, peroxisome proliferators
enhance extracellular signal-regulated kinase
1 and 2 (ERK1 and ERK2) phosphorylation at
tyrosine residues [49]. ppARrI and 12 are
phosphorylated at serine residues 82, 84 and
112, 114 -respectively via MAPK pathway
within the AF-1 domain (these respective
serine residues may represent the same
MAPK consensus sequence) [50, 51]. In
preadipocytes and adipocytes,
phosphorylation of ppARr is stimulated by
insulin and is dependent on the MAPK
pathway [52, 53] whereas prostaglandin F2
inhibits MAPK-dependent phosphorylation of
ppARr [54]. The ppARr phosphorylation
process decreases both ligand binding and
transcriptional activities of target genes and
ultimately arrests the preadipocyte
differentiation into adipocytes [50]. In
addition, phosphorylation at serine residues is
achieved by different ways : phosphorylation
of ppARr1 at serine 84 occurs by ERK2 and
c-jun N-terminal kinase (JNK) [51, 55] ; at
serine 82, by stimulation of epidermal growth
factor receptor via the MAPK-dependent
pathway [53]. Stress protein kinase as
JNKIStress-Activated Protein Kinase
phosphorylates ppARrl in a MAPK
independent manner and subsequently lowers
ppARrl transcriptional level [55]. Finally
ppAR~/() could be phosphorylated even
though no MAPK consensus sequence has
been found and therefore phosphorylation is
processed by a MAPK independent pathway
[51].
PPARS AND LIPID METABüLISM
Fatty acid metabolism
Various target genes implicated in lipid
catabolism mainly in liver are under the
control of PPARa. Fatty acids are released
from lipoprotein particles through the activity
of lipoprotein lipase and then taken up by the
cells.PPARa-dependent lipoprotein lipase