Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611-3008
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ABSTRACT |
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Peroxisomes are
involved in the -oxidation chain shortening of long-chain and
very-long-chain fatty acyl-CoAs, long-chain dicarboxylyl-CoAs, the CoA
esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs, and the CoA
esters of the bile acid intermediates, and in the process, they
generate H2O2. There are two complete sets of
-oxidation enzymes present in peroxisomes, with each set consisting
of three distinct enzymes. The classic PPAR
-regulated and inducible
set participates in the
-oxidation of straight-chain fatty acids,
whereas the second noninducible set acts on branched-chain fatty acids.
Long-chain and very-long-chain fatty acids are also metabolized by the
cytochrome P-450 CYP4A
-oxidation system to dicarboxylic
acids that serve as substrates for peroxisomal
-oxidation. Evidence
derived from mouse models of PPAR
and peroxisomal
-oxidation deficiency highlights the critical importance of the defects in PPAR
-inducible
-oxidation in energy metabolism and in the
development of steatohepatitis.
peroxisomes; fatty acid - and
-oxidation; peroxisomal
proliferator-activated receptor
; peroxisomal biogenesis disorders
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INTRODUCTION |
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FATTY ACIDS (FAs) are ubiquitous
molecules that are pivotal for a variety of cellular processes
including energy storage, synthesis of cellular membranes, and
generation of lipid-containing messengers in signal transduction.
Disturbances in FA metabolism and regulation, especially involving FA
synthesis and oxidation, can contribute to hyperlipidemia, obesity,
insulin resistance, atherosclerosis, and steatohepatitis in
industrialized as well as in developing societies (30,
32). When energy (glucose) intake is abundant, FA synthesis is
enhanced and FA oxidation is reduced to facilitate storage of excess
energy in the form of energy- dense triacylglycerol in adipocytes,
leading to obesity (30, 32). Under conditions of reduced
energy supply, the synthesis of FAs is diminished, culminating in
lipolysis and release of FAs from adipocytes, and the FAs reaching the
liver then undergo oxidation there to generate ketone bodies. These are
then exported out of liver to serve as fuels for extrahepatic tissues
such as cardiac and skeletal muscle (10, 11, 16, 18). Thus
FA oxidation plays a central role in energy homeostasis in that
maintenance of high levels of FA oxidation can result in reduced fat
accumulation despite excess energy consumption (1, 6); in
contrast, reduced FA oxidation can contribute to the development of
obesity as well as hepatic steatosis (Fig.
1).
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FA OXIDATION |
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Oxidation of FAs occurs in three subcellular organelles, with
-oxidation confined to mitochondria and peroxisomes and the CYP4A
catalyzed
-oxidation occurring in the endoplasmic reticulum (14, 20, 21, 28). Some of the key enzymes of these
three FA oxidation systems are transcriptionally regulated by
peroxisome proliferator-activated receptor-
(PPAR
), a member of
the nuclear hormone receptor superfamily (5, 12).
Mitochondrial
-oxidation is responsible for the oxidation of the
bulk of the short (<C8)-, medium
(C8-C12)-, and long
(C12-C20)-chain FAs and, in the process, contributes to energy generation via ATP, producing oxidative phosphorylation (reviewed in Ref. 28). Long-chain FAs
constitute the bulk of dietary fat and thus are the predominant source
of energy under normal feeding conditions and also during
fasting-induced lipolysis. FAs are completely oxidized to acetyl-CoA by
mitochondrial
-oxidation, and the acetyl-CoA subunits so produced
can either condense to form ketone bodies (acetoacetate, acetone, and
-hydroxybutyrate) or degrade to CO2 by the tricarboxylic
acid cycle (28). Mitochondrial
-oxidation is regulated
by carnitine palmitoyltransferase I (CPTI), carnitine concentration,
and also by malonyl-CoA, which inhibits CPTI (26, 28).
CPTI is markedly induced by FAs/fatty acyl-CoAs and by several
structurally different synthetic compounds known as peroxisome
proliferators, which activate PPAR
(9, 25, 28).
The peroxisomal -oxidation is responsible, almost exclusively, for
the oxidation of very-long-chain FAs (>C20) as they cannot be processed by the mitochondrial
-oxidation system due to the absence of very-long-chain fatty acyl-CoA synthetase (20, 28, 34). The peroxisomal
-oxidation system also participates in the metabolism of long-chain dicarboxylic acids, eicosanoids, bile acid
precursors, and the side chains of some xenobiotics (28).
The role of peroxisomal
-oxidation in the synthesis and metabolism
of docosahexanoic acid (DHA) and retroconversion of DHA to
eicosapentaenoic acid has been reviewed recently (28).
There are two complete sets of -oxidation enzymes present in
peroxisomes, with each set consisting of three distinct enzymes (Fig.
2). Straight-chain acyl-CoA oxidase (AOX)
is responsible for the initial oxidation of very-long-chain fatty
acyl-CoAs in the PPAR
-regulated and inducible classic
-oxidation
system, whereas branched-chain acyl-CoA oxidase (BOX) oxidizes
branched-chain fatty acyl-CoAs in the noninducible second system
(20, 28). The three enzymes of the classic peroxisomal
-oxidation cycle, namely AOX, enoyl-CoA
hydratase/L-3-hydroxyacyl-CoA dehydrogenase [L-bifunctional protein (L-PBE)], and
3-ketoacyl-CoA thiolase, are transcriptionally activated by
PPAR
-ligands (28). In the noninducible branched-chain
FA oxidation system, the enoyl-CoAs generated by BOX are dehydrated and
then dehydrogenated by D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase
[D-bifunctional enzyme (D-PBE)]. The third
enzyme of the second system is designated sterol carrier protein x
(SCPx), the NH2 terminal of which exerts thiolytic activity
(20, 28). The separation between two peroxisomal
-oxidation pathways is not rigid after the first desaturation step
catalyzed by specific oxidase (AOX or BOX) as the L- and D-hydroxy intermediates (enoyl-CoA esters of both straight-
and branched-chain FAs) generated in the two
-oxidation systems can be metabolized by the same enzyme, namely the D-PBE,
leaving uncertain the role of L-PBE of the straight-chain
-oxidation system (3, 24, 28). The peroxisomal acyl-CoA
oxidases, which are the first and rate-limiting enzymes of each of the
two
-oxidation pathways in peroxisomes, account for the basic
difference between peroxisomal and mitochondrial oxidation pathways
(20, 28).
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The first step in peroxisomal FA oxidation is directly coupled to the
molecular oxygen, resulting in the cyanide insensitivity of the system,
in contrast to the cyanide sensitivity of the mitochondrial system in
which the first step is directly coupled to an electron-transfer chain
(20). Peroxisomal -oxidation generates
H2O2, whereas mitochondrial
-oxidation
produces energy. Unlike the mitochondrial system, peroxisomal
-oxidation is carnitine independent, and it does not go to
completion as the chain-shortened acyl-CoAs (medium-chain
acyl-CoAs) are exported to the mitochondria for the completion of
-oxidation (20, 28).
The -oxidation of FAs by cytochrome P-450 CYP4A subfamily
starts almost exclusively in smooth endoplasmic reticulum, with the
initial
-hydroxylation step generating a
-hydroxy FA, which is
then dehydrogenated to a dicarboxylic acid in the cytosol (14, 21, 28). Dicarboxylic acid is converted to its CoA derivative by
an acyl-CoA synthetase present in the endoplasmic reticulum. In humans,
long-chain dicarboxylyl-CoAs derived from
-oxidation of FAs are
almost exclusively metabolized by the classic peroxisomal
-oxidation
system, whereas in rats, a significant portion of dicarboxylyl-CoAs
appears to be metabolized via the noninducible branched-chain oxidation
system (28). Although microsomal
-oxidation is
considered a minor pathway for FA metabolism, significant quantities of
dicarboxylic acids can be formed from
-oxidation of long-chain monocarboxylic FAs under conditions of FA overload in the liver; for
example, in diabetes mellitus and in situations in which mitochondrial
-oxidation is impaired.
-Oxidation of FAs can generate reactive oxygen species as the rate of NADPH consumption increases to reduce oxygen to superoxide and/or H2O2
(21). The reactive oxygen species generated during the
-oxidation of FAs to dicarboxylic acids and when these
dicarboxylyl-CoAs undergo
-oxidation within peroxisomes can
contribute to steatohepatitis under certain conditions (6, 13,
26).
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ENZYMES OF THE PEROXISOMAL ![]() |
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Before an FA can be -oxidized by peroxisomes, it must be
activated to its CoA derivative, and this is accomplished by long-chain and very-long-chain acyl-CoA synthetases present in the peroxisomal membrane (20, 28). Long-chain acyl-CoA synthetase, which
activates long-chain FAs, is also present in the mitochondrial outer
membrane and in the endoplasmic reticulum, but very-long-chain acyl-CoA synthetase, which activates very-long-chain FAs, is present in peroxisomal and microsomal membranes but not in mitochondria, accounting for the exclusive
-oxidation of these FAs within the peroxisome.
The first step of the peroxisomal -oxidation cycle is catalyzed by
FAD-containing acyl-CoA oxidases that donate electrons directly to
molecular oxygen, thereby generating H2O2
(20). In the classic PPAR
-regulated and inducible
-oxidation spiral, which deals with straight-chain acyl-CoAs, this
first step is catalyzed by AOX, a single enzyme, in all species
examined (22, 28). AOX is a dimeric protein with a
molecular mass of 140 kDa, which oxidizes CoA esters of straight-chain
FAs, dicarboxylyic acids, and eicosanoids. The human AOX
gene, localized to chromosome band 17q25, is present as a single copy
per haploid genome, and it is structurally similar to the rat gene
(22, 28, 33). Both rat and human AOX proteins contain a
Ser-Lys-Leu peroxisomal targeting signal (PTS1) in the COOH-terminal
end (31, 33). In the second noninducible
-oxidation set
that acts on 2-methyl-branched FAs, such as pristanic acid, which is
derived from phytol contained in food, and on the bile acid
intermediates, di- and trihydroxycoprostanoic acids, which also contain
a 2-methyl substitution in their side chain, the BOX functions as the
first and rate-limiting step in humans (20, 28). Unlike in
humans, the branched-chain
-oxidation spiral in rats can be
initiated by two different noninducible oxidases, namely pristanoyl-CoA
oxidase, which acts on CoA esters of 2-methyl-branched FAs, and
trihydroxycoprostanoyl-CoA oxidase, which uses the bile acid
intermediates as substrates (15, 18).
The second and third steps of peroxisomal -oxidation are catalyzed
by two different bifunctional proteins. The second step is the
hydration of the enoyl-CoAs to 3-hydroxyacyl-CoAs, which are then
dehydrogenated to generate 3-ketoacyl-CoAs in the third step. A single
protein with both enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase
activities, hence called peroxisomal bifunctional enzyme (PBE)
catalyzes these two steps (20, 28). Two different bifunctional proteins exist in peroxisomal matrix: the first is the
L-PBE of the classic PPAR
-ligand inducible
-oxidation
system, and the second is the D-PBE of the branched-chain
noninducible
-oxidation system (20, 28). The substrate
specificities of L-PBE and D-PBE differ in that
both enzymes can metabolize straight-chain enoyl-CoAs as substrates,
but they differ markedly with respect to 3
-, 7
-, and
12
-hydroxy-5
-cholest-24-enoyl-CoA and with respect to 3
-, and
7
-dihydroxy-5
-cholest-24-enoyl-CoA, which appear to be more
desirable as substrates for D-PBE (28).
Finally, the L-PBE and not the D-PBE is
markedly induced by PPAR
ligands in liver.
The last step of the peroxisomal -oxidation process, the thiolytical
cleavage of 3-ketoacyl-CoA into a chain-shortened acyl-CoA and
acetyl-CoA or propionyl-CoA (in case of two methyl-branched FAs), is
catalyzed by two distinct enzymes. These two enzymes are the
3-ketoacyl-CoA thiolase of the classic straight-chain
-oxidation
system and the SCPx of the noninducible branched-chain
-oxidation
system (20, 28). The 3-ketoacyl-CoA thiolase and SCPx
exhibit distinct substrate specificities: the former plays a principal
but restricted role in the
-oxidation of straight-chain 3-ketoacyl-CoAs, and the latter plays a broader role in the cleavage not only of branched-chain FAs and the bile acid intermediates but also
of 3-ketoacyl-CoAs of straight-chain FAs (28).
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REGULATORY ROLE OF PPAR![]() |
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PPAR has been identified as the key regulator of the genes
involved in peroxisomal, mitochondrial, and microsomal FA oxidation systems in liver (5, 10, 12). The induction of some of the
critical enzymes of the
- and
-oxidation systems in liver by
peroxisome proliferators is transcriptionally controlled by PPAR
,
because these effects are abrogated in PPAR
-null mice (14,
17). The ligand-activated PPAR
forms a heterodimer with the
9-cis-retinoic acid receptor RXR, and the PPAR/RXR
heterodimers bind to DNA sequences, termed PPAR response elements
(PPRE), composed of direct repeats of the hexanucleotide sequence
AGGTCA separated by one nucleotide, known as DR-1 response
elements, present in the 5'-flanking region of target genes (reviewed
in Ref 5). PPAR
is highly expressed in the liver and, to a modest
extent, in the kidney and intestinal epithelium, and the levels of
PPAR
appear to reflect the sensitivity of various tissues to the
induction of
-oxidation by synthetic PPAR
ligands
(5). These synthetic ligands are structurally diverse
peroxisome proliferators and include certain hypolipidemic drugs,
phthalate ester plasticizers, herbicides, and leukotriene
D4 receptor antagonists (9, 25, 27). These
synthetic ligands may mimic FAs/fatty acyl-CoAs and other
endogenous/biological ligands of PPAR
(7). Although confirmation-based in vitro assays identified FAs and eicosanoids as
biological PPAR
ligands (7), observations in AOX-null
mice strongly imply that substrates of AOX such as very-long-chain fatty acyl-CoAs are the most likely PPAR
activators in vivo
(6). Thus PPAR
appears to be a xenosensor as well as a
sensor of fluxes in certain lipid moieties in liver (7).
In conditions associated with excess energy consumption, acetyl-CoA
generated from glucose is used for FA synthesis, and its subsequent
conversion to triglycerides leads to adiposity (30, 32).
Evidence indicates that adipogenesis is facilitated by PPAR
, a
member of the PPAR subfamily (4, 26), and an increase in
adipogenesis occurs to store triglycerides under conditions of
decreased PPAR
activity and reduction of FA oxidation, implying a
cross-talk between these two receptors.
The molecular mechanisms by which PPARs and other nuclear receptors
achieve transcriptional activation in a gene-, tissue-, and
species-specific manner are the subjects of intense investigation in
recent years (for review, see Ref. 8). The current models call for participation of a series of cofactors (accessory proteins) that associate with nuclear receptors in a ligand-dependent fashion (8). During the past 6 years, several "coactivator"
proteins for nuclear receptors have been identified (8).
Some of these possess histone acetyltransferase activity, and they also
recruit other proteins with similar activity, indicating their role in chromatin modification (8). There is also emerging
evidence suggesting a role for cofactor-mediated histone methylation
and possibly RNA methylation in the transcriptional activation by nuclear receptors (4, 35). Elucidation of the tissue- and cell-specific mechanisms of transcriptional activation of genes involved in peroxisomal -oxidation is important for a greater appreciation of the importance of lipid homeostasis in health and
disease. Such studies may lead to new insights into the modulation of
FA oxidation and in developing measures to limit disease processes.
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PEROXISOMAL BIOGENESIS DISORDERS AND ![]() |
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Peroxisomal disorders in humans manifesting as disturbances in
lipid metabolism represent a group of inherited diseases in which there
is an impairment of peroxisomal -oxidation resulting from defects in
one or more enzymes (31, 34). These disorders, classified
on the basis of biochemical defects, generally fall into three
categories depending on whether there is a generalized (group
A), multiple (group B), or single (group C)
loss of peroxisomal functions (31, 34). Groups
A and B are mostly related to defects in
posttranslational import of peroxisomal matrix proteins due to
mutations in PEX genes (PEX5, and
PEX7), whose gene products, peroxins (PEX proteins), are
involved in peroxisome biogenesis (30, 33). PEX5 and PEX7
serve as receptors for peroxisomal targeting signals PTS1 and PTS2,
respectively, and mutations in these PEX genes will disrupt
peroxisomal import of proteins, leading to serious defects in
peroxisomal
-oxidation (2, 31, 34). Zellweger syndrome,
neonatal adrenoleukodystrophy, and infantile Refsum's disease are
examples of group A with generalized defects in peroxisome
assembly, manifesting in the functional loss of many peroxisomal
enzymes (34). Abnormalities in the peroxisomal
-oxidation pathway in these disease states involve specifically the
metabolism of very-long-chain FAs, long-chain dicarboxylic acids,
pristanic acid, and certain prostaglandins among others (2, 28,
34). Furthermore, deficiency of the peroxisomal
-oxidation
system affects the biosynthetic pathway of DHA, and reduced levels of
DHA affect structure of cell membranes, particularly of neuronal
tissues, accounting for dysmyelination, retinopathy, and psychomotor
retardation observed in Zellweger patients (34). Rhizomelic chondrodysplasia punctata with dysfunction of the
PEX7 gene, which encodes PTS2 receptor, is an example of
group B disease, and peroxisomes of these patients lack all
proteins, which are imported via the PTS2 receptor. These patients
manifest defects in ether phospholipid metabolism due to abnormalities
in dihydroxyacetonephosphate acyltransferase and
alkyldihydroxyacetonephosphate synthase (34).
Peroxisomal disorders, reflecting the loss of a single peroxisomal
function due to loss/mutation in a single gene, represent group
C. Diseases in this category representing peroxisomal
-oxidation include x-linked adrenoleokodystrophy (X-ALD),
straight-chain AOX deficiency, D-PBE deficiency, and
thiolase deficiency (34). To date, no patients have been
discovered manifesting deficiency of L-PBE, BOX, or SCPx.
X-ALD, a most frequent peroxisomal genetic disorder, presents either as
a lethal childhood form or as a mild "Addison's-only" form
(34). In X-ALD, very-long-chain FAs accumulate due to
impaired peroxisomal
-oxidation in most part due to a defect in an
80-kDa peroxisomal membrane protein called adrenoleukodystrophy protein (ALDP), which belongs to the ATP-binding cassette
transporter superfamily (34). This protein transports
C26:0 CoA esters across the peroxisome membrane into
peroxisome matrix. There is inadequate information regarding the
pathological and pathogenetic manifestations in patients with defects
in peroxisomal
-oxidation. A major unresolved issue is how
individuals with genetic defects in peroxisomal
-oxidation or
PPAR
-inducible genes react to nutritional and environmental stress
and sensors.
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MOUSE MODELS OF PEROXISOMAL ![]() ![]() |
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To gain a better understanding of the pathophysiology of
peroxisomal deficiency disorders, several investigators have begun generating gene knockout mouse models. Sustained activation of PPAR
and the induction of PPAR
-responsive genes that participate in lipid
catabolism in liver by synthetic or natural PPAR
ligands manifest in
hepatic peroxisome proliferation and liver tumor development in both
rats and mice (6, 9, 25). Because available evidence suggests the refractoriness of human liver cells to peroxisome proliferation (9), it is implied that the carcinogenic
risk to humans from exposure to synthetic PPAR
ligands is somewhat negligible. The reasons for the nonresponsiveness of human liver cells
to peroxisome proliferation are not clear but may be attributed, in
part, to lower PPAR
levels, among others (14, 23). The identity of PPAR
target genes involved in hepatic lipid catabolism is well established. The use of gene targeting to disrupt PPAR
and
some of the genes involved in peroxisome biogenesis and in the
peroxisomal
-oxidation system has provided new insights about the
role of peroxisomal
-oxidation in energy metabolism (2, 3, 6,
15, 17, 19, 24, 29).
A knockout mouse model for Zellweger syndrome was generated by
disrupting the PEX5 gene (3), which encodes
Pex5p, the cytoplasmic shuttle receptor for the import of most of
peroxisomal matrix proteins (31). PEX5/
mice lack
peroxisomes and manifest severe defects characteristic of Zellweger
patients (3). A mouse model for X-ALD has been developed
by disrupting X-ALD gene, which encodes ALDP, which is a
peroxisomal membrane protein and transporter (19). The
X-ALD mouse exhibits reduced
-oxidation of very-long-chain FAs,
culminating in significant accumulations of these insoluble FAs in many
tissues (19). At the
-oxidation level, the first two
genes of the classic inducible
-oxidation set, namely AOX and
L-PBE, have been knocked out in mice using homologous
recombination (6, 24). Likewise, mice lacking the second
and third genes, namely D-PBE and SCPx, of the noninducible
second
-oxidation set have also been generated (3, 15,
29). Several recent reviews have described these models in
detail and point to their usefulness as experimental systems for
detailed investigations of the pathogenetic alterations during the
lifespan of these genetically altered animals and for testing
therapeutic interventions (2, 9, 26, 28).
Two major observations are worth noting here: 1) the
disruption of AOX, the first and the rate-limiting enzyme of the
classic -oxidation set, leads to dramatic activation of PPAR
(6), and 2) the disruption of the peroxisomal
-oxidation pathway, either proximal to or distal to classic AOX,
fails to hyperactivate PPAR
(19, 24). Mice with a
disrupted AOX gene (AOX
/
) exhibit, during the
first 2-4 mo of life, increased serum levels of very-long-chain FAs, growth retardation, hepatomegaly with severe microvesicular steatohepatitis, and lipogranulomatous reaction (6). AOX
knockout mice reveal age-progressive hepatocellular regeneration
commencing in the periportal region and extending toward the
centrizonal region of the liver lobule (6). The
regenerated hepatocytes reveal a profound degree of spontaneous
peroxisome proliferation, implying that substrates of AOX left
unmetabolized in the absence of AOX function as PPAR
ligands and
thus cause sustained hyperactivation of this transcription factor
(6). The AOX null mouse model serves as a paradigm for
several important pathophysiological processes (6). The
microvesicular steatosis and steatohepatitis developing during early
life in these AOX-null mice is most likely due to very-long-chain FA
toxicity and to increased levels of dicarboxylyic acids produced as a
result of highly induced CYP4A
-oxidation enzymes resulting from
PPAR
activation (6, 10). In the absence of peroxisomal
-oxidation due to AOX deficiency, these dicarboxylic acids cannot be
metabolized, highlighting the importance of peroxisomal
-oxidation
in the pathogenesis of steatohepatitis under conditions of
PPAR
-mediated increased
-oxidation (6). Support for
the role of dicarboxylic acids and PPAR
hyepractivation is also
derived from the observation that mice deficient in both AOX and
PPAR
do not exhibit hepatic steatosis, implying that failure
to induce CYP4A enzymes abrogates the production of these toxic
derivatives. Mice lacking L-PBE, the second enzyme of this classic
-oxidation set, do not develop steatohepatitis and do not
show any evidence of sustained PPAR
activation, implying that
disruption of this
-oxidation system distal to AOX will not result
in spontaneous peroxisome proliferation (24).
Also of considerable significance is that mice deficient in PPAR and
those deficient in both PPAR
and AOX exhibit severe hepatic
steatosis when subjected to fasting for 24-72 h, indicating that a
defect in PPAR
-inducible FA oxidation accounts for severe FA
overload in liver, causing steatosis, in contrast to the wild-type mice, which respond by enhancing FA oxidation (10, 11, 16, 18). These models point to the criticality of PPAR
-inducible FA oxidation systems in energy metabolism and in the development of
hepatic steatosis. It remains to be established if abnormalities in
PPAR
levels and PPAR
-inducible oxidation systems contribute to
hepatic steatosis in humans. These observations suggest that maintenance of high levels of FA oxidation reduces fat accumulation in
liver and most likely prevents unwanted energy storage in extrahepatic tissues. Thus pharmacological enhancement of FA oxidation can be
accomplished by augmenting mitochondrial
-oxidation directly or by
judicious pharmacological inhibition of AOX, which may lead to
transcriptional activation of PPAR
and upregulation of the mitochondrial oxidation system, as seen in AOX-null mice.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. K. Reddy, Dept. of Pathology, Northwestern Univ. Medical School, 303 East Chicago Ave., Chicago, IL 60611-3008 (E-mail: jkreddy{at}northwestern.edu).
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