Proc. Natl. Acad. Sci. USA
Vol. 96, pp. 7473–7478, June 1999
A critical role for the peroxisome proliferator-activated receptor ?
(PPAR?) in the cellular fasting response: The PPAR?-null
mouse as a model of fatty acid oxidation disorders
(nuclear hormone receptors?lipid metabolism?transcriptional control?dietary regulation)
TERESA C. LEONE*†, CARLA J. WEINHEIMER*†, AND DANIEL P. KELLY*‡§¶
*Center for Cardiovascular Research, Departments of‡Medicine and§Molecular Biology and Pharmacology, Washington University School of Medicine,
St. Louis, MO 63110
Communicated by William H. Daughaday, University of California at Irvine, Balboa Island, CA, April 29, 1999 (received for review April 5, 1999)
transcription factor, the peroxisome proliferator-activated
receptor ? (PPAR?), plays a pivotal role in the cellular
metabolic response to fasting. Short-term starvation caused
hepatic steatosis, myocardial lipid accumulation, and hypo-
glycemia, with an inadequate ketogenic response in adult mice
lacking PPAR? (PPAR????), a phenotype that bears remark-
able similarity to that of humans with genetic defects in
mitochondrial fatty acid oxidation enzymes. In PPAR????
mice, fasting induced the hepatic and cardiac expression of
PPAR? target genes encoding key mitochondrial (medium-
chain acyl-CoA dehydrogenase, carnitine palmitoyltrans-
ferase I) and extramitochondrial (acyl-CoA oxidase, cyto-
chrome P450 4A3) enzymes. In striking contrast, the hepatic
and cardiac expression of most PPAR? target genes was not
induced by fasting in PPAR????mice. These results define a
critical role for PPAR? in a transcriptional regulatory re-
sponse to fasting and identify the PPAR????mouse as a
potentially useful murine model of inborn and acquired
abnormalities of human fatty acid utilization.
We hypothesized that the lipid-activated
Starvation triggers a complex array of adaptive metabolic
responses. A prominent feature of the energy-metabolic re-
ketones for energy production (1–4) and an augmentation in
the capacity for mitochondrial fatty acid oxidation (FAO) in
tissues with high oxidative energy demands such as heart and
liver (5). The importance of the fasting-inducible capacity for
cellular lipid utilization is underscored by the dramatic phe-
notype of human inborn errors in mitochondrial FAO enzymes
(6). Children afflicted with genetically determined enzymatic
defects in the FAO pathway typically are asymptomatic under
normal feeding conditions. However, short-term fasting, such
as that associated with an infectious illness, precipitates a
dramatic and often fatal clinical picture characterized by
hypoketotic hypoglycemia, liver dysfunction, and cardiomyop-
athy (6–8). Postmortem studies of FAO enzyme-deficient
patients have demonstrated marked intracellular accumula-
tion of neutral lipid in liver and heart. The capacity to oxidize
fats is also diminished in several common acquired cardiac
diseases including cardiac hypertrophy and myocardial isch-
emia (9–17). The molecular pathogenesis of target organ
dysfunction from inherited and acquired alterations in cellular
FAO has not been elucidated.
A previous study in rodents demonstrated that the hepatic
expression of genes encoding mitochondrial FAO enzymes is
induced, at the transcriptional level, in response to fasting (5).
This transcriptional regulatory response likely plays a key role
in the fasting-induced augmentation of FAO capacity in liver
and other oxidative tissues. The mechanisms involved in the
fasting-induced transcriptional activation of FAO enzyme
genes are unknown. However, recent studies have identified a
role for a nuclear receptor, the peroxisome proliferator-
genes encoding mitochondrial FAO enzymes in heart and liver
(16, 18–23). PPAR? first was identified based on its control of
genes encoding peroxisomal FAO enzymes in response to
peroxisome proliferators such as fibric acid derivatives (24).
PPAR? now is known to regulate the transcription of genes
encoding peroxisomal, mitochondrial, and certain cytochrome
P450 enzymes (18, 24–26) involved in long-chain FAO. Fatty
acids and peroxisome proliferators are among the compounds
known to activate PPAR? (27–29), which binds its cognate
elements as a heterodimeric partner with the retinoid X
receptor (30). The results of recent studies have indicated that
endogenous PPAR? ligands are metabolized by peroxisomal
(31) and mitochondrial (18) FAO pathways, providing further
evidence that fatty acid intermediates activate PPAR? in vivo.
Accordingly, PPAR? as a lipid-activated nuclear receptor is an
excellent candidate for mediating the physiologic and dietary
control of genes encoding cellular fatty acid utilization en-
zymes. We sought to test the hypothesis that PPAR? is
involved in the metabolic response to fasting. We predicted
be unable to increase the capacity for cellular fatty acid
utilization in the context of short-term starvation.
Animal Studies. The PPAR????and PPAR????mice were
a generous gift of Frank J. Gonzalez (National Cancer Insti-
tute, Bethesda, MD) and have been described (32, 33). The
PPAR????and PPAR????lines were pure-bred on an sv129
background (32). All experiments were performed with mice
ranging in age from 12 to 16 weeks (20–30 g). Male and female
littermate or age-matched mice were separated into individual
cages at the beginning of each fasting experiment. Fasting was
initiated at 9:00 a.m. For the gene expression studies, fasting
was initiated at 5:00 p.m. The mice were fasted for 24 h or 48 h
as indicated in the text. Control mice (fed ad libitum) and
fasted mice were kept in identical light?dark cycles. The
control mice were allowed free access to standard lab chow
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PNAS is available online at www.pnas.org.
Abbreviations: PPAR, peroxisome proliferator-activated receptor;
FAO, fatty acid oxidation; NEFA, nonesterified free fatty acids;
MCAD, medium-chain acyl-CoA dehydrogenase; CPT I, carnitine
palmitoyltransferase I; ACO, acyl-CoA oxidase; CYP, cytochrome
P450; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
†T.C.L. and C.J.W. contributed equally to this work.
¶To whom reprint requests should be addressed at: Center for
Cardiovascular Research, Washington University School of Medi-
cine, 660 South Euclid Avenue, Campus Box 8086, St. Louis, MO
63110. e-mail: email@example.com.
(Diet 5053; Purina). At the time of harvest, animals were killed
by CO2inhalation and tissue from liver and cardiac ventricles
were rapidly dissected free, snap-frozen in liquid nitrogen, and
stored at ?80°C until processed for isolation of RNA or lipid
extraction. All animal experiments were conducted in strict
accordance with the National Institutes of Health guidelines
regarding humane treatment for the care and use of laboratory
animals and were reviewed and approved by the Animal
Studies Committee of Washington University School of Med-
Mouse tail vein blood glucose levels were determined by use
of a standard clinical blood glucometer (B-Glucose Analyzer;
Hemocue, Angelholm, Sweden). Plasma ?-hydroxybutyrate
levels were determined by the Washington University School
of Medicine Diabetes and Research Training Center RIA
Core Laboratory. Serum nonesterified fatty acid (NEFA)
levels were determined by the Core laboratory of the General
Clinical Research Center at Washington University School of
Tissue Histology Studies. After harvest, liver and heart were
sliced quickly and snap-frozen in a cryomold for cutting. The
sections were stained with oil red O and counterstained with
RNA-Blotting Studies. Isolation of total RNA and the
protocol for Northern blotting have been described (34).
32P-labeled probes were derived from the following cDNAs:
mouse medium-chain acyl-CoA dehydrogenase (MCAD; ref.
16); rat liver-form carnitine palmitoyltransferase I (L-CPT I)
generated by reverse transcription–PCR (RT-PCR) amplifi-
cation using primers 5?-TCCCCACTCAAGATGGCAGAG-
GCT-3? (sense) and 5?-CTTCCGTGTGGCTCAGGGGTTT-
AC-3? (antisense); rat muscle-form CPT I (M-CPT I) gener-
ated by RT-PCR using primers 5?-GCGGAAGCACACC-
AGGCAGTA-3? (sense) and 5?-ATGTTTGGAAGCTATA-
GAGCA-3? (antisense); rat acyl-CoA oxidase (ACO; ref. 33)
and rat cytochrome P450 4A3 (CYP 4A3; ref. 33); and gly-
ceraldehyde-3-phosphate dehydrogenase (GAPDH; ref. 35).
Statistical Methods. Statistical comparisons were made by
using Student’s t test or ANOVA coupled to a Fisher’s test. A
statistically significant difference was defined as P ? 0.05.
The Hepatic and Cardiac Lipid Homeostatic Response to
Fasting Is Altered in PPAR????Mice. To explore the role of
PPAR? in the response to fasting, the metabolic phenotype of
PPAR????mice was investigated after short-term starvation.
As described previously, PPAR????mice do not exhibit an
overt phenotype during the first 6 months of life but have been
shown to express reduced levels of FAO enzymes and to lack
a peroxisomal, biogenic response to peroxisome proliferators
(32, 36). Our studies focused on heart and liver, organs known
to increase the capacity for fat oxidation in response to fasting.
Age- and strain-matched PPAR????and PPAR????animals
were subjected to a 48-h fast (see Methods). At the end of the
fasting period, hearts and livers were harvested from both
groups and characterized. All of the PPAR????animals (n ?
29) survived the fast whereas 2?32 PPAR????mice died
between 24 and 48 h of fasting. The PPAR????mice that died
were both male. After a 24-h fast, the livers of the PPAR????
mice that survived the fast were slightly enlarged and appeared
mice (Fig. 1A). Histologic sections of livers from fasted
demonstrated marked micro- and macrovesicular lipid intra-
cellular droplet accumulation (Fig. 1B). Examination of liver
sections from the fasted PPAR????mice revealed that the
distribution of lipid droplet accumulation was massive and
homogeneous rather than exhibiting a regional pattern (data
not shown). TLC analysis of lipid extracted from the livers of
the fasted PPAR????mice (compared with fed PPAR????
controls) revealed that the majority of accumulated lipid was
in the triglyceride fraction (data not shown). The degree of
hepatic lipid accumulation was not significantly different in
male compared with female fasted PPAR????mice. These
results indicate that fasting induces a significant derangement
in hepatic lipid balance in the PPAR?-null mice.
The gross appearance and weights of the hearts of fasted
PPAR????animals was not significantly different than that of
fasted PPAR????mice or fed PPAR????controls. Histologic
analysis of the myocardium of the fasted mice revealed patchy
oil red O-positive regions in the PPAR????mice but was
consistently negative in the PPAR????mice (data not shown),
indicating that as in liver, the cellular lipid homeostatic
response to fasting is altered in the hearts of PPAR????mice.
The levels of circulating NEFA were determined in the
(?SD) NEFA levels were 938 ? 154 ?M in the PPAR????
mice and 862 ? 200 ?M in the PPAR????group (P ? not
significant). After a 48-h fast, mean NEFA levels were 1,541 ?
343 ?M in PPAR????mice compared with 838 ? 195 ?M in
PPAR????mice, a significant difference (P ? 0.001). These
results suggest that in addition to a reduced capacity for FAO,
PPAR????mice exhibit abnormally high fasting, circulating
free fatty acids, both of which could contribute to the hepatic
and cardiac lipid accumulation.
The Glucose Homeostatic Response to Fasting Is Altered in
PPAR????Mice. Children with inherited defects in mitochon-
drial FAO develop severe hypoglycemia during fasting (6, 7).
Hypoglycemia occurring in the context of defective mitochon-
drial FAO likely is due to a combination of glycogen depletion
and a blunted gluconeogenic response. To determine whether
PPAR????mice exhibit a similar abnormality in glucose
homeostasis, circulating glucose levels were delineated in
age-matched male and female PPAR????and PPAR????
mice during a 48-h fast. Blood glucose levels in the PPAR????
animals exhibited an initial drop during the first 24 h of fasting
followed by a rebound increase returning to near normal levels
by 48 h. In fasted PPAR????mice, the initial fall in mean
blood glucose levels was significantly greater than that of the
PPAR????mice, dropping from 122 ? 2 mg?dl to 51 ? 2
mg?dl during the first 24 h of fasting (Fig. 2). Compared with
the PPAR????group, the blood glucose levels of fasted
PPAR????mice were significantly lower at all time points
measured (24, 36, and 48 h of fasting; Fig. 2). During the
second 24 h of fasting, the PPAR????mice did exhibit a
rebound increase in blood glucose levels. The mean blood
glucose levels were not significantly different in male com-
not shown). Thus, the glucose homeostatic response is abnor-
mal in the PPAR????mice as manifested by a hypoglycemic
response to fasting.
The Ketogenic Response to Fasting Is Blunted in
PPAR????Mice. During a period of fasting, substrate for the
production of ketone bodies is derived from acetyl-CoA
moieties produced mainly by mitochondrial ?-oxidation. Ac-
cordingly, a characteristic feature of the fasting-induced hy-
poglycemia associated with defective capacity for mitochon-
drial FAO is an inadequate ketogenic response (6). Indeed,
hypoketotic hypoglycemia is a well described clue to establish-
ing the diagnosis of human genetic defects in FAO (6). To
explore the possibility that the reduced capacity for mitochon-
drial FAO in PPAR????mice would result in an inadequate
ketogenic response to fasting, plasma ?-hydroxybutyrate levels
were measured in PPAR????and PPAR????mice after a
48-h fast. Mean fasting plasma ketone levels were markedly
induced in fasted PPAR????mice (Fig. 3). In striking con-
trast, fasting did not increase the plasma ketone levels in
PPAR????mice despite development of hypoglycemia (Fig.
3). These were no significant gender differences in the plasma
7474Medical Sciences: Leone et al.Proc. Natl. Acad. Sci. USA 96 (1999)
ketone levels in the control and fasted PPAR????and
PPAR????mice (data not shown).
The Fasting-Induced Activation of Hepatic and Cardiac
PPAR? Target Gene Expression Is Markedly Blunted in
PPAR????Mice. The expression of genes encoding mitochon-
drial FAO enzymes is increased in the liver of fasted rats (5).
Given that in PPAR????mice the cellular lipid metabolic
response to fasting is altered, we hypothesized that PPAR?
serves to activate the transcription of hepatic and cardiac FAO
the expression of PPAR? target genes encoding mitochondrial
[MCAD; liver (L-) or muscle (M-), CPT I], peroxisomal
of livers from fasted PPAR????(Left) and PPAR????(Right) mice. The livers were harvested rapidly from age-matched PPAR????and
PPAR????mice after a 24-h fast. The left hepatic lobes are shown. (B) Photomicrographs demonstrating the histologic appearance of the livers
of PPAR????mice under fed and fasted conditions. Frozen tissue sections were prepared from the livers of PPAR????mice after a 24-h fast
(FASTED) and age-matched PPAR????controls fed ad libitum (FED). The sections were stained with oil red O. The red droplets indicate positive
staining for neutral lipid.
Accumulation of intracellular lipid in the liver of fasted PPAR????mice. (A) Representative photograph demonstrating the appearance
ing. Mean blood glucose levels (ordinate) of age-matched PPAR????
and PPAR????mice at various time points during a 48-h fast. Mean
values were based on 21 PPAR????mice (6 male; 15 female) and 30
PPAR????mice (12 male; 18 female). ? indicates a statistically
significant difference (P ? 0.001; Fisher’s test) compared with the
corresponding value obtained in age-matched PPAR????animals.
PPAR????mice exhibit a hypoglycemic response to fast-FIG. 3.
mice. Bars ? mean ? SE serum ?-hydroxybutyrate (?-HBA) levels
determined in age-matched PPAR????and PPAR????mice after a
48-h fast compared with the fed ad libitum state. ? denotes a significant
difference (P ? 0.05) compared with the value of the fed PPAR????
group. Values are based on at least six mice per group and two
The ketogenic response to fasting is blunted in PPAR????
Medical Sciences: Leone et al.Proc. Natl. Acad. Sci. USA 96 (1999) 7475
(ACO), and cytochrome P450 (CYP 4A3) FAO enzymes was
characterized in the livers and hearts of control (fed) and
24-h-fasted PPAR????and PPAR????mice. Fasting induced
the steady-state levels of mRNA encoding MCAD, L-CPT I,
and ACO 2- to 4-fold in liver of the PPAR????mice (Fig. 4).
As shown recently by others (37), fasting induced the hepatic
expression of the CYP 4A3 gene 15- to 20-fold in PPAR????
mice (Fig. 4). In striking contrast, the fasting-mediated induc-
tion of MCAD, ACO, and CYP 4A3 gene expression was
abolished in PPAR????mice. The fasting response of the
L-CPT I gene, however, was preserved in PPAR????mice.
In the hearts of PPAR????mice, fasting caused a modest
but significant induction of the expression of PPAR? target
genes encoding M-CPT I, MCAD, and ACO (1.5- to 3.5-fold;
Fig. 5). The fasting response of the PPAR? target genes
(M-CPT I, MCAD, and ACO) was abolished in the hearts of
PPAR????mice (Fig. 5). Taken together, these data indicate
that PPAR? is necessary for the fasting-induced expression of
target genes involved in hepatic and cardiac mitochondrial and
extramitochondrial fatty acid utilization. Moreover, these re-
sults suggest that the observed cellular lipid imbalance in
PPAR????mice is a result, at least in part, of an inadequate
capacity to meet increased demands for cellular FAO in heart
Our results identify a critical role for PPAR? in the gene
transcriptional regulatory response to short-term starvation.
target genes encoding cellular FAO enzymes is abolished in
PPAR????mice. (A) Representative autoradiographs of Northern
blot analyses performed with total RNA (15 ?g?lane) isolated from
the livers of fed control (C) and 24-h-fasted (F) littermate PPAR????
(???) and PPAR????(???) mice. The cDNA probes are denoted
on the left (abbreviations defined in the text). The signal for GAPDH
mean fasting fold induction compared with the values of fed littermate
controls based on phosphorimager analysis of Northern blots de-
scribed in A. All values were normalized to the signal for GAPDH.
? denotes a significantly (P ? 0.05) higher mean signal intensity
compared with the corresponding fed control values. The values are
based on a minimum of nine animals per group and four independent
The fasting-induced hepatic expression of most PPAR?
genes is altered in PPAR????mice. (A) Representative autoradio-
graphs of Northern blot analyses performed with total RNA (15
?g?lane) isolated from the hearts of fed control (C) and 24-h-fasted
(F) littermate PPAR????(???) and PPAR????(???) mice. The
cDNA probes are denoted on the left. The signal for GAPDH is shown
as a control for loading and RNA integrity. (B) Bars represent mean
fasting fold induction compared with fed littermate controls after
normalization to the GAPDH signal based on phosphorimager anal-
(P ? 0.05) higher mean signal intensity compared with corresponding
fed control values. The values are based on a minimum of six animals
per group and three independent experiments.
The fasting-induced cardiac expression of PPAR? target
7476 Medical Sciences: Leone et al.Proc. Natl. Acad. Sci. USA 96 (1999)
PPAR? is shown to be required for the fasting-activated
expression of target genes involved in mitochondrial and
extramitochondrial FAO in liver and heart, tissues known to
increase FAO rates during short-term starvation. Our findings
are consistent with a recent report by Kroetz et al. (37),
demonstrating that PPAR? mediates the induced hepatic
expression of CYP 4A genes in response to starvation and in
the diabetic state. Accordingly, PPAR? is one of only a few
transcription factors known to be involved in the cellular
response to fasting. Recently, the transcription factor ADD1?
SREBP was shown to confer fasting-mediated transcriptional
down-regulation of the gene encoding fatty acid synthase
(FAS), an enzyme involved in lipid synthesis (38). Taken
together, these results indicate that distinct transcriptional
regulatory pathways are involved in two key metabolic re-
sponses to fasting: induction of cellular fatty acid utilization
and reduction of lipid synthesis.
The dramatic fasting phenotype of the PPAR????mice
reflects a defective cellular lipid homeostatic response. The
fasting-induced accumulation of intracellular lipid demon-
strated here is consistent with the known reduction in the
hepatic and cardiac expression of PPAR? target genes encod-
fatty acid utilization coupled with a loss of the fasting-induced
expression of several key FAO enzyme genes results in a
mismatch between cellular lipid import and utilization, leading
to cellular lipid accumulation in the PPAR????mice. In
support of this proposed mechanism, we demonstrated re-
cently that in the context of a perturbation of mitochondrial
long-chain fatty acid import caused by pharmacologic inhibi-
tion of CPT I, PPAR????mice develop marked hepatic and
cardiac lipid accumulation (33). In this report, we also found
abnormally high fasting, circulating NEFA levels in
PPAR????mice. Our data do not allow us to determine
whether elevated-fasting serum NEFA levels in PPAR????
mice contribute to the observed hepatic and cardiac lipid
The phenotype of the fasted PPAR????mice unveils an
important role for PPAR? in glucose and energy homeostasis.
In contrast to extramitochondrial FAO pathways, mitochon-
drial ?-oxidation is an important source of ATP and acetyl-
the mitochondrial FAO cycle is a precursor for ketogenesis. In
PPAR????mice, in which the fasting-mediated induction of
mitochondrial FAO enzyme expression is altered, the capacity
for ATP and ketone production is limited. As predicted, the
PPAR????mice exhibit a severely blunted ketogenic response
to fasting despite the development of hypoglycemia. Interest-
ingly, hypoketotic hypoglycemia is a diagnostic hallmark of
inherited defects in mitochondrial FAO enzymes in humans
(6). The hypoglycemic response of the fasted PPAR????mice
likely reflects both a depletion of hepatic glycogen and a
reduced capacity for gluconeogenesis because of a decrease in
the intracellular levels of acetyl-CoA, a potent activator of the
gluconeogenic pathway (39, 40).
Inborn errors in mitochondrial ?-oxidation enzymes are an
important cause of inherited episodic hypoglycemia, hepatic
dysfunction, cardiomyopathy, and skeletal myopathy during
childhood (6–8). The clinical manifestations of genetic defects
in FAO enzymes are ‘‘stress’’-induced; affected children are
usually asymptomatic until faced with a dietary or physiologic
condition that dictates an increased reliance on the oxidation
of fats for energy. For example, during a period of fasting,
affected children often develop a clinical episode or ‘‘crisis’’
characterized by the precipitous onset of symptoms related to
multiorgan toxicity. The pathogenesis and pathophysiology of
end-organ abnormalities that occur in children with inborn
errors in FAO pathway enzymes are poorly understood but
likely involve energy starvation and the effects of potentially
toxic lipid intermediates. PPAR????mice exhibit fasting-
induced lipid accumulation in liver and heart in association
with hypoketotic hypoglycemia, a phenotype that bears a
striking resemblance to that of humans with genetic defects in
mitochondrial FAO enzymes. Recently, mice null for the
mitochondrial FAO enzyme, long-chain acyl-CoA dehydroge-
nase (LCAD), also were shown to have a metabolic phenotype
similar to that of humans with inherited defects in FAO (41).
aimed at characterizing the pathogenesis of this important
group of inherited childhood disorders as well as several
common acquired human cardiovascular diseases known to be
associated with reduced capacity for mitochondrial FAO such
as pressure overload-induced cardiac hypertrophy and myo-
cardial ischemia (9–14).
We recently have demonstrated that PPAR????mice ex-
hibit a gender-influenced response to pharmacologic inhibi-
tion of CPT I (33). The metabolic abnormalities of the
etomoxir-treated PPAR????mice were shown to be more
severe in males compared with females. In addition, gender-
related serum and hepatic lipid abnormalities recently were
reported in aged PPAR????mice (42). In contrast, the
fasting-induced phenotype of the PPAR????mice described
here was not influenced by gender. It is possible that CPT I
inhibition induces a more severe perturbation in hepatic and
cardiac metabolism compared with that of fasting, such that
the gender effect was manifest only in the context of the
former. Alternatively, CPT I inhibition may induce a distinct
gender-influenced metabolic pathway that is not activated by
In summary, our results identify PPAR? as a key factor in
the cellular metabolic response to fasting. We propose that in
response to fasting and other physiologic conditions known to
cause a mismatch between cellular lipid uptake and utilization,
PPAR? is activated by an endogenous lipid ligand to induce
the orchestrated expression of genes involved in FAO and,
thus, increase the capacity for cellular fatty acid utilization—a
key metabolic response that serves to maintain cellular lipid
balance in tissues such as liver that increase fatty acid uptake
PPAR????mice should be useful in the investigation of the
pathogenesis and treatment of inherited and acquired human
We thank Kelly Hall for assistance with preparation of the manu-
DK45416 and HL58493 and American Heart Association Grants EIA
95001150 and GIA 9750199N.
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