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hydrolyses triglycerides present in very lowdensity
lipoproteins and stimulates LDL
uptake [56]. PPARa increases the
transcription of apolipoproteins AI, AIl [57,
58] and inhibits the transcription of
apolipoprotein CIlI [59] resulting,
respectively, in modulation of high density
lipoprotein-mediated cholesterol transport and
in increase of lipoprotein lipase activity.
Within the cens, intrace11ular transport is
facilitated by stimulation of ppARadependent
target genes such as fatty acid
transport protein, fatty acid translocase and
hepatic cytosolic fatty acid-binding protein
[60, 61]. Uptake of long-chain fatty acids
involves activation into acyl coA thioesters by
acyl-coA synthetase [60] and subsequently
degradation by the peroxysomal ~-oxidation
pathway which enzymes are regulated by
PPARa [62-65]. Long-chain fatty acids import
into mitochondria is regulated by ppARadependent
carnitine palmitoyl transferase l
[66-68]. Furthermore, link between
mitochondria metabolism and ppARadependent
regulation has been provided from
the identification of functional PPRE on
promoters of the ~-oxidative medium chain
acyl-coA deshydrogenase gene [69] and 3­
hydroxy-3-methylglutary1-coA synthase gene
[70], the rate limiting enzyme of ketogenesis.
Data from ppARa knoutout mice also
demonstrated that ppARa positively regulates
constitutive mitochondrial ~-oxidation [71]. In
these mice, feeding with a high fat diet leads
to lipid accumulation in the liver reflecting the
reduction of mitochondrial long chain fatty
acid import. It must however be note that
ppARa knoutout mice have metabolic
changes including high cholesterol levels and
low ~-oxidation [72] and changes in
lipoprotein metabolism [73]. Final1y, liver
ppARa transcriptional level is under the
control of circadian levels of glucocorticoids
levels which participate to energy
mobilization [74]. Fasting or glucocorticoids
stress also induce ppARa expression in
hepatocytes [74, 75].' In addition to its
implication in liver, ppARa also alters
Hervé Schohn et al.
thermogenesis in adipose tissue by modulating
the expression of uncoupling protein 1 and 2
[76, 77]. Uncoupling protein-1 in rat brown
adipocytes is also regulated by PPARy [76].
Adipocyte differentiation
Adipocyte differentiation is a complex process
leading to changes in gene expression [78-80].
This process involves CCAATT/enhancer
binding proteins [81-83] and PPARs. PPARy
is implicated in terminal adipocyte
differentiation. Murine ppARy2 was initia11y
cloned as a component of an adipocytespecific
transcription factor ARF6 and found
to be the heterodimer mPPARy2lRXRa [84].
It regulates the expression Of adipocyte fatty
acid-binding protein aP2 [84], and
phosphoenolpyruvate carboxykinase [85],
which are markers of terminal adipocyte
differentiation. Likewise, ppARy regulates the
expression of lipoprotein lipase, fatty acid
transport protein and fatty acid translocase in
an adipocytic-specific manner [56, 61].
Fina11y, there is a dramatic increase in the
expression of ppARy-dependent and
CCAAT/enhancer binding protein-dependent
target genes during cell differentiation and
maturation [86, 87]. Activation of ppARy
with thiazo1idinedione also increases the
number of small preadipocytes in rat white
adipose tissue [88]. Subsequently, these ce11s
undergo growth arrest' and subterminal
differentiation into adipocytes. The initial step
of preadipocyte proliferation may depend on
activation of ppAR~/o [89] In any NIH-3T3
fibroblasts lineage, a model of preadipocyte
differentiation into adipocytes, treatment with
cAMP elevating agents and activation of
ppAM promote mitotic clonai expansion
[89]. In addition, in 3T3C2 fibroblasts,
ppARo activated by fatty acids induce ppARy
target -gene [90].
The pivotaI role of ppARy was demonstrated
by different ways : Retroviral expression of
ppARy2 induces adipocyte differentiation in
cultured mouse fibroblasts [91].