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Research Communications |
* Hypertension Research, Max Delbrück Center for Molecular Medicine, 13122 Berlin-Buch, Germany;
Division of Molecular Biology, Roslin Institute, Roslin EH 25 9PS, U.K.; and
Centre for Genome Research, University of Edinburgh, Edinburgh EH9 3JQ, U.K.
1Correspondence: Hypertension Research, Max Delbrück Center for Molecular Medicine, Franz-Gross-Haus, 134 D, Wiltbergstr. 50, 13122 Berlin-Buch, Germany. E-mail: binasb{at}mdc-berlin.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: metabolism • heart • hypertrophy • gene targeting • mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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.
Fatty acid binding proteins (FABPs), a widely expressed and genetically
related family of small cytosolic proteins that specifically and
reversibly bind LCFAs, may function as the principal vehicles of
cytosolic LCFA transport (2,
3
; reviewed in ref 4
). It has, however,
turned out to be surprisingly difficult to obtain firm evidence for
this notion (5)
, probably because FABP-mediated LCFA fluxes require an
LCFA concentration gradient that is not easily maintained or
reconstituted in vitro. Support for the ability of FABPs to
facilitate LCFA transport in living cells has come only recently from
transfection studies with intestinal and liver FABP (6,
7)
, but a
contribution of these or other FABPs to LCFA transport in
vivo, where higher LCFA fluxes occur, remains uncertain. All
current in vivo data on FABPs are correlative and also
compatible with other functions, such as cell signaling or protection
against LCFA cytotoxicity (reviewed in ref 5
). The existence of at
least one unrelated protein potentially capable of transporting LCFAs
within the cell (8)
further cautions that it is not sufficient to
demonstrate a functional ability of an FABP in vitro to draw
conclusions about its biological importance.
Deletion of endogenous gene expression within its normal in
vivo context is potentially the most convincing way to demonstrate
a functional significance, although this approach carries the risk of
unwanted compensation (9)
. As FABPs show interesting expression
patterns that reflect the division of labor between various organ
systems, such a strategy may also create useful animal models for
investigating regional aspects of LCFA metabolism. Heart-type FABP
(H-FABP) is extremely abundant in mature cardiomyocytes, cells normally
fueled mainly by mitochondrial oxidation of LCFAs; it is also abundant
in red skeletal muscle, moderately expressed in numerous other
peripheral organs, and completely absent in liver, white fat, and
intestine (10
11
12
13)
. In cardiac and red skeletal muscle, H-FABP appears
to be the only representative of its family. The expression pattern and
assumed significance for LCFA transport suggest this protein is
important for peripheral LCFA metabolism.
To both clarify the role of a prototypical FABP in LCFA transport and create a genetic model with which to investigate the physiological and pathophysiological significance of cardiac and other peripheral LCFA fluxes, we deleted the H-FABP gene in laboratory mice by gene targeting technology. The resulting phenotype confirms the viability of this approach by demonstrating for the first time a requirement for an FABP in cellular LCFA utilization. H-FABP-deficient mice show a dramatic switch in cardiac fuel selection and provide a new genetic model of metabolic cardiac hypertrophy. Combined with the analysis of blood plasma metabolites and of the physical performance of H-FABP-deficient mice, the data reveal a major role of H-FABP for fuel metabolism in the whole body.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The long (6 kb) homology arm was isolated as an
EcoRI-ScaI fragment from the 5' flank of the
H-FABP gene, end-filled, cloned into the end-filled HindIII
site of pBluescript, then excised with EcoRV and
SalI and transferred into the short arm/HPRT construct.
Finally, a NotI fragment containing the 2 kb SP-thymidine
kinase minigene (TK) was inserted to complete the replacement type
targeting vector depicted in Fig. 1
A. After linearization with SalI, electroporation into
embryonic stem (HM1) (15)
cells, and selection with HAT/ganciclovir,
homologous recombination was identified by polymerase chain reaction
amplification of a 2.5 kb diagnostic fragment (see Fig. 1A
)
using primers 5'-taaagcgcatgctccagactgcc and 5'-cattgttccatcgccagcacatc
at an annealing/extension temperature of 68°C in the presence of 5%
glycerol/2% DMSO. Two independent ES cell clones were used for
blastocyst injection and yielded germ line chimeras after embryo
transfer. Experiments were performed with mice of a 129xBalb/c
background; comparisons were made between mice of the same age (3
months if not otherwise indicated) and sex, mostly male. The
institutional authorities approved all animal experiments.
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Southern, Northern, and Western blotting
DNA and total RNA were isolated by proteinase K
digestion/isopropanol precipitation and the TRIZOL (Life Technologies,
Paisley, U.K.) procedure, respectively. Southern and Northern blotting
were performed according to standard methods (16)
using random-primed
32P-labeled DNA probes: for Southern blots, a 2.2
kb-BamHI-EcoRI genomic fragment just downstream
of the short homology arm (Fig. 1A
); and for Northern blots,
cDNAs coding for H-FABP (17)
and other FABPs (4)
, mouse FAT (18)
, rat
muscle CPT1 (19)
, rat LCAD (long-chain acyl CoA dehydrogenase) (20)
,
and rat atrial natriuretic peptide (ANP) (21)
. Positive controls for
FABP mRNA expression were white fat (ALBP), olfactory bulb (B-FABP),
skin (E-FABP), and liver (L-FABP). Northern blots were quantified with
a FUJIX BAS2000 phosphorimager. For Western blotting, snap-frozen
tissues were powdered, boiled in 10% sodium dodecyl sulfate, and
microfuged; supernatants were used for protein determination (BCA;
Pierce, Rockford, Ill.) and 15% sodium dodecyl sulfate-polyacrylamide
gel electrophoresis. After transfer to nitrocellulose and blocking with
1% bovine serum albumin/0.01% Tween 20, filters were incubated with a
1:100–1:500 dilution of a rabbit anti-mouse H-FABP antiserum, washed,
and developed using Amersham's ECL chemiluminescence kit.
Diets
Diets were purchased from SNIFF (Soest, Germany). The standard
diet contained ca. 45% digestible carbohydrates, 22% protein
(supplemented with methionine and lysine), 4.5% fat, the remainder
vitamins, minerals, and nondigestible. In one set of experiments, a
ketogenic diet containing 35% fat (here, a 60/40 mix of porcine lard
and hardened sunflower oil), 15% casein, 40% of a mix of cellulose
and Aerosil, and 10% of standard addition of minerals, vitamins, and
methionine was used.
Tracer studies
125I-labeled
15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP),
obtained in ethanol, was dried and redissolved in 0.9% NaCl/1%
delipidated bovine serum albumin at 200 µCi/ml.
[1-14C]-2-deoxy-D-glucose was diluted to 20
µCi/ml with 0.9% NaCl. Approximately 20 µCi of
125I-BMIPP or 4 µCi of
14C-deoxyglucose were injected into the tail vein
of mice that had been fasted overnight. After 5 and 30 min (end of
labeling), aliquots of blood were withdrawn from the retro-orbital vein
and counted; blood concentrations of 125I
remained unchanged, whereas those of 14C
decreased to 39 ± 12% (wild-type) and 33 ± 8%
(nullizygotes). Mice were killed by cervical dislocation and the organs
were excised (blood was released from heart chambers), rinsed in
isotonic saline, blotted onto filter paper to remove excessive fluid,
weighed, and the radioactivity was counted directly
(125I) or after liquefaction with a tissue
solubilizer (14C). Uptakes are given as
(R1/W)/R2; R1 is the radioactivity of the organ piece, W its wet weight
(grams), and R2 the radioactivity of 10 µl of blood taken 5 min after
injection; division by R2 corrects for small differences in injected
radioactivities or plasma volumes.
Metabolite measurements
Blood was withdrawn from the retro-orbital vein, mixed with
EDTA, and an aliquot was used for glucose determination in a clinical
laboratory after brief storage at 4°C. The bulk was centrifuged at
low speed and the supernatant was either frozen for later determination
of lactate, cholesterol, triglycerides and ß-hydroxybutyrate in a
clinical laboratory or used after less than 24 h at 4°C to
determine nonesterified fatty acids with the half micro kit from
Boehringer Mannheim (Mannheim, Germany).
Distribution of muscle fiber sizes
Paraffin sections of mouse hearts were stained by the periodic
acid Schiff-reaction; fibers parallel to the level of sectioning, with
diameters falling into the indicated 2.5 µM intervals, were counted.
Data are pooled for three mice (12 months old) per genotype; the same
number of sections was analyzed per mouse and a comparable number of
fibers was counted on each section.
Swim training
Mice of both genotypes were collectively placed into a 56 x 37 cm water thermostat fixed at 35°C. Training was for 10
(experiment 1) or 30 (experiment 2) min initially, with daily increases
of 10 min from day 2 (experiment 1) or day 4 (experiment 2) onward, up
to a final training period of 90 min, which was maintained until the
end.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), hemizygous
(H-FABP+/-) and nullizygous
(H-FABP-/-) mice were derived (Fig. 1B
). Nullizygous mice are viable and show no macroscopic
abnormalities; they exhibit a normal sex ratio, weight gain, and
fertility, and raise their offspring with no apparent problems.
Histological sections of heart, liver, skeletal muscle, and kidney from
3-month-old mice appear normal. The absence of H-FABP mRNA and protein
in tissues of nullizygous mice was confirmed by Northern (Fig. 1C
) and Western (Fig. 1D
) blotting, respectively.
Levels of H-FABP mRNA are decreased to ~50% in hemizygous mice. No
compensatory expression of closely related (ALBP, B-FABP, E-FABP) or
other (L-FABP) members of the FABP gene family was detected by Northern
blotting in heart and skeletal muscle (results not shown). Some other
mRNA levels related to fatty acid metabolism were also compared in
wild-type vs. H-FABP-deficient hearts: FAT (fatty acid translocase)
(18)
, 70 ± 6 vs. 50 ± 7; CPT1 (carnitine
palmitoyltransferase 1) (19)
, 41 ± 2 vs. 41 ± 5; and LCAD
(20)
, 41 ± 5 vs. 35 ± 0.4 (values normalized to GAPDH mRNA
levels and given as arbitrary units ± SE;
n=4 to 9 per genotype). The amount and expression pattern of
mitochondrial RNAs as assessed with a full-length mitochondrial DNA
probe were unchanged. These results suggest that the capacities for
membrane transport and ß-oxidation of LCFAs are maintained in the
absence of H-FABP.
To investigate LCFA utilization in vivo, the uptake of
125I-BMIPP, a non-ß-oxidizable LCFA analog
(22)
, was determined for various organs. As shown in Fig. 2
A, liver uptakes of 125I-BMIPP are
identical in normal and H-FABP null mice, whereas the normally high
cardiac uptake is greatly reduced in the knockout mice. Similar results
were obtained from skeletal muscles (M. soleus), although
the control uptake into this tissue was relatively low as the mice did
not exercise during labeling. This shows that at least in the heart,
H-FABP has to be present to extract LCFA efficiently from the
bloodstream. The effect on fatty acid uptake is specific, as the uptake
of the glucose tracer analog 14C-deoxyglucose is
not reduced in knockout mice (Fig. 2A
). Instead, there is a
substantial increase of cardiac 14C-deoxyglucose
uptake in H-FABP-deficient mice, suggesting that glucose substitutes
for LCFA as an energy substrate in this organ.
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Additional evidence for a reduction in peripheral LCFA usage was
sought by investigating plasma levels of key energy substrates under
standard conditions (free access to mixed diet) and conditions favoring
fatty acid oxidation (starvation, ketogenic diet) (Fig. 2B
).
In H-FABP-deficient mice, free fatty acid plasma levels are increased
compared with wild-type mice under all conditions, indicating a reduced
utilization. Furthermore, the increase of ß-hydroxybutyrate levels
seen with a high-fat/carbohydrate-free diet is much more pronounced in
the H-FABP nullizygous mice, consistent with the notion that part of
the excess plasma LCFAs is converted to ketone bodies in the liver,
where LCFA utilization is not reduced. Glucose levels of
H-FABP-deficient mice showed a greater decrease on starvation or
high-fat diet than wild-type controls, suggesting that carbohydrates
are used more intensely in H-FABP-deficient mice. Lactate levels were
slightly lower in the knockout mice but only significantly so in
fasting mice. No differences were observed for triglyceride and
cholesterol levels.
Pharmacological inhibition of mitochondrial (23)
or cellular (24)
fatty acid uptake, a fat-free diet (25)
, as well as inborn diseases of
fatty acid oxidation and transport (26
27
28)
have all been associated
with cardiac hypertrophy. Therefore, we investigated whether
H-FABP-deficient mice develop a similar abnormality. Figure 3
A shows a 38fold (P<0.0005, n=6 per
genotype) increase of ANP mRNA, a prototypical marker of cardiac
hypertrophy (29)
, in cardiac ventricles of 3-month-old H-FABP-deficient
mice. By 10–12 months of age, H-FABP-deficient, but not wild-type,
hearts developed overt histological changes consistent with cardiac
hypertrophy, which include a massive enlargement of myocyte nuclei
(Fig. 3B
) and an increase of mean muscle fiber diameter
(from 9.5 to 14.1 µM; P<0.0005, n=3 per
genotype) (Fig. 3C
). These changes are limited to the septum
and near-luminal muscle layers (particularly of the left ventricle) of
the heart chambers. Total heart weights and heart/body weight ratios of
old nullizygous mice are increased moderately but significantly
(P<0.05) by ~10%, as compared with controls, reflecting
the localized character of the hypertrophy.
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To test the limit of compensation, 24 nullizygous and 23
wild-type mice 3 months of age were subjected to an exercise regimen of
repetitive swimming (30)
. Six nullizygous mice (25%) and one wild-type
animal (<5%) died during swimming (Fig. 4
A). Survivors were observed for signs of exhaustion.
`Exhaustion' was difficult to assess during swimming, but the
phenomenon was easily assessed in the post-training period. Normal
animals started grooming immediately after swimming; they moved around
and their fur dried quickly. Exhausted animals did not move, their fur
remained wet, and it took them up to 60 min to recover (Fig. 4B
). Fifteen nullizygous mice showed exhaustion once or
repeatedly on 14 out of 30 training days, whereas only seven wild-type
animals were exhausted on 3 days (Fig. 4A
). These results
strongly suggest that H-FABP deficiency becomes deleterious under
circumstances requiring heart and skeletal muscle work. Figure 4
suggests that decompensation (i.e., exercise intolerance) arises
acutely, as there is no cumulative effect of training; correspondingly,
light microscopy did not reveal differences between the hearts and
skeletal muscles of trained nullizygous and wild-type mice.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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5)
. The data in Fig. 2A
show
that H-FABP expression is indeed a prerequisite for a high flux of
LCFAs in the heart and that there is no redundancy in that function.
Cardiac levels of mRNAs encoding the sarcolemmal and outer
mitochondrial membrane LCFA transporters, FAT and CPT1, as well as the
mitochondrial ß-oxidation enzyme, LCAD, are maintained. Given the
previously published results (summarized in refs 4
and 5) that in the
heart, H-FABP is mainly expressed in the soluble cytoplasm of
cardiomyocytes (rather than endothelium or connective tissue), that it
binds LCFAs, lacks enzymatic function, and its expression parallels
LCFA oxidation, our results provide the main missing piece of evidence
to conclude that H-FABP directly mediates LCFA transport in
cardiomyocytes.
The dramatic metabolic shifts that accompany H-FABP deficiency (Fig. 2B
) demonstrate that H-FABP expression is a major
determinant of the pattern of fuel consumption in the body. These
changes cannot be due to cardiac involvement alone but are likely to
also involve other organs normally expressing H-FABP, notably skeletal
muscles (Fig. 2A
). Like the heart, skeletal muscles do not
appear to express other FABPs as judged by Northern and Western
blotting. LCFA transport deficiency in H-FABP nullizygous mice is
clearly distinguished from all known cases of heritable CPTI defects,
from systemic carnitine deficiency, and from pharmacological CPTI
inhibition. Unlike these conditions, H-FABP deficiency does not impair
hepatic ß-oxidation but rather stimulates it, explaining why
H-FABP-deficient mice tolerate starvation well and providing for the
first time an animal model with which to study the role of peripheral
LCFA oxidation. It is also different from those hereditary human CPTII
defects that do not present with overt liver disease in that the latter
are only partial and affect the enzyme throughout the body (see ref 31
for a review of the CPT system and its mutations). It will be
interesting to see in more detail how in H-FABP-deficient mice, heart
and skeletal muscle fibers cope with impaired LCFA metabolism and
cooperate with the liver to overcome it. The mechanism of increased
glucose uptake, the metabolic fate of the glucose, the energy status of
H-FABP-deficient hearts and other peripheral organs (especially
skeletal muscles) at rest and work, and the precise reason for exercise
intolerance all deserve further investigation.
At old age, H-FABP-deficient mice develop a regional cardiac
hypertrophy, which is restricted to the septum and ventricle muscle
layers near the lumina of the heart chambers. This picture is
reminiscent of the asymmetrical septal hypertrophy (ASH) occurring in
humans deficient for CD36, a cardially expressed putative plasma
membrane LCFA transporter (27)
. H-FABP deficiency may therefore provide
a model for some human cardiomyopathies thought to be caused by
depressed myocardial LCFA utilization (26)
and may be used to
investigate the currently unknown mechanism linking altered fuel
selection and cardiac hypertrophy. Furthermore, our finding raises the
possibility that mutations in the H-FABP gene may be responsible for
unexplained cases of hereditary ASH.
The lack of redundancy for H-FABP function contrasts with observations
on mice lacking the adipocyte FABP (aP2, or ALBP), which suggests a
pathophysiological role for ALBP. ALBP-deficient mice activate the
E-FABP gene in their adipocytes and on a normal diet do not exhibit a
metabolic defect. However, on a high fat diet, they fail to develop
insulin resistance (9)
, possibly because E-FABP expression copes only
with basal but not increased needs for LCFA transport. Increased LCFA
transport may be a prerequisite for insulin resistance. Thus, although
ALBP-deficient mice do not prove a role of ALBP or E-FABP in LCFA
transport, their phenotype is consistent with this role. In contrast,
H-FABP-deficient mice directly prove the importance of FABP for LCFA
transport. They should be suitable models with which to examine the
relationship between cellular LCFA fluxes and muscle insulin
sensitivity under both normal and high-fat dietary intake. Such
experiments will require that the H-FABP gene deletion be back-crossed
onto a C57/Bl6 inbred background.
In conclusion, H-FABP-deficient mice establish a major role of
H-FABP in cellular lipid transport. They provide the first
demonstration of a physiological role for a member of the large and
widely expressed FABP gene family and suggest that other FABPs may also
be suitable targets to manipulate LCFA metabolism. H-FABP-deficient
mice may be useful when investigating some clinically relevant effects
of reduced LCFA utilization, such as cardiac hypertrophy (see above),
improved ischemic heart function (32)
, reduced high blood pressure
(33)
, or increased insulin sensitivity (33
; foregoing discussion), and
to assess the contribution of peripheral tissues vs. liver/white fat in
these phenomena. Other hypothesized functions of H-FABP, such as the
protection of reperfused myocardium (5)
or of arterial walls (34)
from
the toxic effects of fatty acids or modulation of proliferation and
differentiation (35)
may now also be verified using this model.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations: ANP, atrial natriuretic peptide; ASH,
asymmetrical septal hypertrophy; HPRT, hypoxanthine phosphoribosyl
transferase; LCAD, long-chain acyl CoA dehydrogenase; LCFA, long-chain
fatty acid, H-FABP, heart-type fatty acid binding protein, BMIPP,
[125I]-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic
acid; PCR, polymerase chain reaction.
Received for publication December 14, 1998.
Revision received January 14, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Y. Fu, N. Luo, and M. F. Lopes-Virella Oxidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages J. Lipid Res., December 1, 2000; 41(12): 2017 - 2023. [Abstract] [Full Text]
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