Biology Reference
In-Depth Information
expression according to the availability of fatty acids.
53
The endogenous
ligands for PPARs are fatty acids or compounds derived from fatty acids, such
as certain prostaglandins. There are three major isoforms of PPAR (
a
,
b
/
d
,
and
g
). Upregulated PPAR
a
in the liver increases fatty acid oxidation and
overall fatty acid availability. Fatty acid storage as triacylglycerol in adipose tis-
sue is also upregulated by activated PPAR
g
. As PPAR ligands, the
n
-3 series
polyunsaturated fatty acids are more potent than the
n
-6 series or the saturated
fatty acids. The PPAR protein, with its ligand bound, binds to the Retinoid
X Receptor (RXR), whose ligand is all-
cis
-retinoic acid, a derivative of vita-
min A. PPAR
g
is considered as one of the master regulators of adipogenesis
and macrophage function.
53,54
Activated PPAR
g
/RXR heterodimers bind
to peroxisome proliferator response elements (PPREs) and trigger the expres-
sion of PPAR
g
-targeted genes.
55-57
The coordinated activation of these
PPAR
g
-targeted adipogenic genes leads to a flux of fatty acids from the cir-
culation and other tissues into adipocytes. PPAR
g
transcriptional activity is
also modulated by interaction with a number of different coactivators or core-
pressors, such as NCoR and SMRT.
54,58,59
The PPAR
g
-repressive com-
plexes possess histone deacetylase or methyltransferase activities through
which they remodel the chromatin structure and repress gene transcription.
54
In activated macrophages, PPAR
g
-repressive complexes function to mediate
the expression of inflammatory genes for immune responses.
54
In these ways,
PPAR
g
governs the function of adipocytes and macrophages and helps to
achieve whole-body energy balance, and has become a central focus of obesity
and diabetes research.
The PPAR system has aroused intense interest because of its potential
for pharmacological manipulation. Thiazolidinediones, synthetic ligands for
PPAR
g
, have been widely in use for the treatment of diabetes. These ligands
act by increasing the ability of adipose tissue to store excess fatty acids as
triacylglycerol. Thus, circulating fatty acid concentrations are reduced, and
tissues such as skeletalmuscle are able toutilizemoreglucosebecauseof reduced
substrate competition. More recently, drugs have been designed to activate
PPAR
d
. Although the physiological role of PPAR
d
has not been clear, studies
have shown that it canmarkedly increase themuscle's oxidativecapacity.
60
Fur-
thermore, PPAR
d
agonists have been shown to improve HDL-cholesterol
concentrations and reduce insulin resistance in monkeys and humans.
61
Our previous studies showed that in the nucleus,
b
-arrestin-1 regulates
histone modification and gene transcription through its interaction with
p300, the same cofactor necessary for hypoxia inducible factor (HIF)-
mediated transcription.
62
Recently, we reported that
b
-arrestin-1 modifies
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