Liver fatty acid binding protein gene ablation potentiates hepatic cholesterol
accumulation in cholesterol-fed female mice
Gregory G. Martin,1Barbara P. Atshaves,1Avery L. McIntosh,1
John T. Mackie,2Ann B. Kier,2and Friedhelm Schroeder1
Departments of1Physiology and Pharmacology and2Pathobiology, Texas A&M University, College Station, Texas
Submitted 11 November 2004; accepted in final form 23 August 2005
Martin, Gregory G., Barbara P. Atshaves, Avery L. McIntosh,
John T. Mackie, Ann B. Kier, and Friedhelm Schroeder. Liver
fatty acid binding protein gene ablation potentiates hepatic cholesterol
accumulation in cholesterol-fed female mice. Am J Physiol Gastro-
intest Liver Physiol 290: G36–G48, 2006. First published August 25,
2005; doi:10.1152/ajpgi.00510.2004.—Although liver fatty acid bind-
ing protein (L-FABP) is postulated to influence cholesterol homeosta-
sis, the physiological significance of this hypothesis remains to be
resolved. This issue was addressed by examining the response of
young (7 wk) female mice to L-FABP gene ablation and a cholesterol-
rich diet. In control-fed mice, L-FABP gene ablation alone induced
hepatic cholesterol accumulation (2.6-fold), increased bile acid levels,
and increased body weight gain (primarily as fat tissue mass). In
cholesterol-fed mice, L-FABP gene ablation further enhanced the
hepatic accumulation of cholesterol (especially cholesterol ester, 12-
fold) and potentiated the effects of dietary cholesterol on increased
body weight gain, again mainly as fat tissue mass. However, in
contrast to the effects of L-FABP gene ablation in control-fed mice,
biliary levels of bile acids (as well as cholesterol and phospholipids)
were reduced. These phenotypic alterations were not associated with
differences in food intake. In conclusion, it was shown for the first
time that L-FABP altered cholesterol metabolism and the response of
female mice to dietary cholesterol. While the biliary and lipid phe-
notype of female wild-type L-FABP?/?mice was sensitive to dietary
cholesterol, L-FABP gene ablation dramatically enhanced many of the
effects of dietary cholesterol to greatly induce hepatic cholesterol
(primarily cholesterol ester) and triacylglycerol accumulation as well
as to potentiate body weight gain (primarily as fat tissue mass). Taken
together, these data support the hypothesis that L-FABP is involved in
the physiological regulation of cholesterol metabolism, body weight
gain, and obesity.
cholesterol ester; triacylglycerol; mouse
LIVER FATTY ACID BINDING PROTEIN (L-FABP) is one of a large
family of nonenzymatic, lipid-binding proteins present in high
amounts (3–5% of liver cytosol protein, 100–400 ?M) in liver
cytosol (for a review, see Ref. 18). Because of its high affinity
for fatty acids, much interest has focused on the physiological
role of L-FABP in fatty acid metabolism (for a review, see Ref.
18). However, increasing data suggest that L-FABP may also
play a role in intracellular cholesterol dynamics.
First, structural studies show that compared with other
members of this protein family, L-FABP has a ligand-binding
site at least twice as large, sufficient to accommodate mole-
cules the size of cholesterol and bile acids (for a review, see
Ref. 27). Indeed, in vitro studies show that L-FABP binds
cholesterol with a dissociation constant as low as 0.3 ?M (for
a review, see Ref. 22), and chemically blocking the L-FABP
ligand-binding site inhibits sterol binding (31). A variety of in
vitro radioligand and fluorescence displacement studies show
that L-FABP also binds bile acids (for a review, see Ref. 28).
On the basis of cross-linking studies of photoreactive bile
acids, it has been suggested that L-FABP is a major cytoplas-
mic bile acid binding protein (7).
Second, L-FABP selectively enhances intermembrane cho-
lesterol transfer from isolated plasma membranes (24) and
from isolated plasma membranes to isolated mitochondria in
vitro (for a review, see Ref. 9). Chemically blocking the
L-FABP ligand-binding site inhibits intermembrane sterol
transfer activity (31). Furthermore, L-FABP enhances micro-
somal conversion of exogenous cholesterol to cholesterol esters
by acyl CoA:cholesterol acyl transferase (ACAT) in vitro (6).
Finally, L-FABP overexpression in cultured cells increases
cholesterol uptake, intermembrane transfer, and intracellular
cholesterol ester mass (for a review, see Ref. 14). Inhibiting
cholesterol binding abolishes L-FABP-mediated enhancement
of cellular cholesterol uptake in transfected cells and inhibits
L-FABP-mediated cholesterol transfer from the plasma mem-
brane to the endoplasmic reticulum for cholesterol esterifica-
tion in transfected cells (14).
Despite the above studies, relatively little is known regard-
ing the physiological relevance of L-FABP to cholesterol
dynamics. It was recently noted that L-FABP is upregulated as
much as four- to fivefold in male sterol carrier protein (SCP)-
x/SCP-2 gene-ablated mice, concomitant with decreased liver
cholesterol ester mass (26) and hypersecretion of cholesterol in
bile (10). While the latter finding suggests that L-FABP may be
the cholesterol transporter responsible for the biliary choles-
terol hypersecretion in SCP-2/SCP-x gene-ablated mice, the
complexity of the SCP-2/SCP-x gene-ablated mouse precludes
discrimination of the relative contributions of L-FABP upregu-
lation, SCP-2 ablation, and SCP-x ablation to the cholesterol
phenotype. Both SCP-2 and SCP-x are soluble proteins that
also bind, transfer, or utilize cholesterol (for a review, see
To begin to resolve these issues, the present investigation
utilized sexually mature, female L-FABP gene-ablated mice to
test the hypothesis that L-FABP may have a physiological role
in cholesterol metabolism in response to high dietary choles-
terol. It was shown that 1) L-FABP gene ablation increased
hepatic cholesterol and bile acids as well as biliary lipid levels
(bile acids, cholesterol, and phospholipids); 2) L-FABP gene
ablation potentiated the effects of dietary cholesterol to syner-
Address for reprint requests and other correspondence: F. Schroeder, Dept.
of Physiology and Pharmacology, TVMC, Texas A&M Univ., College Station,
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The costs of publication of this article were defrayed in part by the payment
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Am J Physiol Gastrointest Liver Physiol 290: G36–G48, 2006.
First published August 25, 2005; doi:10.1152/ajpgi.00510.2004.
0193-1857/06 $8.00 Copyright © 2006 the American Physiological Societyhttp://www.ajpgi.orgG36
gistically redirect cholesterol and bile acid from the biliary
lipid pool to hepatic accumulation of free and even more so
cholesterol esters as well as bile acids; and 3) L-FABP gene
ablation potentiated the effect of cholesterol on increased body
weight gain and fat tissue mass (FTM).
MATERIALS AND METHODS
Materials. Protease inhibitor cocktail for mammalian tissues was
purchased from Sigma-Aldrich (St. Louis, MO). Protein Assay Dye
Reagent Concentrate was obtained from Bio-Rad Laboratories (Rich-
mond, CA). Silica gel G thin-layer chromatography plates were
purchased from Analtech (Newark, DE). Reference lipids were ob-
tained from Nu-Chek-Prep (Elysian, MN). Biliary lipids were deter-
mined as follows: bile acids (Bile Acids-L3K Assay kit, Diagnostic
Chemicals; Oxford, CT), free cholesterol (Wako kit no. 274-47109,
Wako Diagnostics; Richmond, VA), and phospholipids (Wako kit no.
990-54009, Wako Diagnostics). All reagents and solvents used were
of the highest available grade and were cell culture tested.
Animals. Experimental protocols for the use of laboratory animals
were approved by the University Lab Animal Care Committee and
met American Association for Accreditation of Laboratory Animal
Care guidelines. L-FABP null (L-FABP?/?) C57BL/6 mice were
obtained as previously documented (17). Mice were maintained on a
standard low-fat (5% of calories from fat) pelleted rodent chow
(Teklad Rodent Diet W8604, Harlan Teklad; Madison, WI), housed in
a temperature-controlled (25°C) facility on a 12:12-h light-dark cycle,
and allowed free access to food and water.
Dietary study. Because of the gender-dependent differences in
expression of enzymes involved in bile acid metabolism (for a review,
see Ref. 25) and the greater sensitivity of female mice to dietary
branched-chain lipids such as cholesterol (for a review, see Ref. 25),
the dietary study was performed with 7-wk-old female L-FABP
gene-ablated (L-FABP?/?) mice along with age- and sex-matched
L-FABP wild-type (L-FABP?/?) littermates as controls. Mice were
housed individually and acclimated for 1 wk to water and a control-
defined pelleted diet fed ad libitum. The control diet was a modified
AIN-76A phytol-free and phytoestrogen-free pelleted rodent diet (5%
of calories from fat, no. D11243, Research Diets; New Brunswick,
NJ) (2). Once acclimated to the modified control diet (Research Diets
no. D11243), mice were then either continued for 5 wk on the control
pelleted diet (Research Diets no. D11243) or placed on an isocaloric
cholesterol-rich pelleted diet. The latter was comprised of the same
control pelleted diet (5% of calories from fat, no. D01091702, Re-
search Diets) supplemented with 1.25% cholesterol as formulated by
the manufacturer. Of the total of 32 mice used, 16 animals were
maintained on the control diet and 16 animals were exposed to the
1.25% cholesterol diet. Each diet consisted of two separate groups of
animals: eight L-FABP?/?females and eight L-FABP?/?females.
Throughout the course of the study, at the same time of day, the mice
were weighed every other day. At the same time, all pellets and
fragments of rodent food were removed from each cage and weighed,
and this weight was subtracted from the weight of pelleted food
initially placed in the feeding bin to determine the amount of food
consumed by the animal during each 2-day period. These measure-
ments were taken at exactly the same time of day every 2 days
throughout the course of the dietary study to minimize any differences
in amounts of food spilled or overall pattern of food consumption.
However, because mice spill food, it is difficult to precisely measure
food intake by this method. Furthermore, any differences in diurnal or
other pattern of food intake throughout each day/night were not
measured by this method. There were no significant differences in the
amount of food consumed by the animals on either diet, as described
below in RESULTS. This indicated that the mice did not exhibit any
significant dietary preferences. After being weighed, animals were
returned to their respective cages, and preweighed amounts of the
appropriate pelleted diet were placed in the feeding bins.
Animal euthanization, tissue collection, and morphometric analy-
sis. At the beginning and conclusion of the dietary study, mice were
examined by dual-energy X-ray absorptiometry (DEXA) to quantify
the amount of body FTM and bone-free lean tissue mass (LTM) as
described previously (2). Before death, each animal was fasted for
12 h, weighed, anesthetized, and again examined by DEXA. Blood
was then collected from the mouse via cardiac puncture, and the blood
was immediately processed to serum and stored at ?80°C. The animal
was euthanized by cervical dislocation; the tissues of interest were
removed, flash frozen with dry ice, and stored at ?80°C for subse-
quent analysis. The liver was removed, and a small piece of the liver
was used immediately for histological analysis. The remainder of the
liver was divided into small portions, flash frozen with dry ice, and
stored at ?80°C for subsequent analysis. The gall bladder was also
removed from each animal; the bile was collected, flash frozen with
dry ice, and stored at ?80°C for subsequent biliary lipid analysis.
Histological analysis was performed as described previously (2). The
severity of fatty vacuolation in hepatocytes was scored as follows: 0,
normal; 1, minimal fatty change; 2?, mild fatty change; 3?, moderate
fatty change; and 4?, severe fatty change.
Western blot analysis. Primary antibodies against the following
proteins involved in cholesterol metabolism were obtained as follows:
1) rabbit polyclonal anti-mouse scavenger receptor class B type I
(SR-BI) from Novus Biologicals (Littleton, CO); 2) goat polyclonal
anti-mouse low-density lipoprotein (LDL) receptor, anti-human acyl-
CoA:cholesterol acyltransferase 1 (ACAT-1), goat polyclonal anti-
human cholesterol 7?-hydroxylase (CYP7A1), goat polyclonal anti-
human sterol 27-hydroxylase (CYP27A1), rabbit polyclonal anti-
human peroxisome proliferator-activated receptor-? (PPAR-?), rabbit
polyclonal anti-human sterol regulatory element binding protein 1
(SREBP-1), rabbit polyclonal anti-human farnesoid X receptor
(FXR), goat polyclonal anti-human liver X receptor-? (LXR-?), goat
polyclonal anti-mouse short heterodimer partner protein (SHP), goat
polyclonal anti-mouse bile salt export protein (BSEP), goat polyclonal
anti-human multidrug resistance protein 2 (MRP2), and rabbit poly-
clonal anti-mouse fatty acid transport protein 1 (FATP-1) from Santa
Cruz Biotechnology (Santa Cruz, CA); 3) rabbit polyclonal antisera to
recombinant rat L-FABP, rabbit anti-recombinant mouse SCP-2, rab-
bit anti-recombinant mouse acyl-CoA binding protein (ACBP), rabbit
anti-recombinant mouse SCP-x, and rabbit anti-porcine aspartate
aminotransferase (AAT, i.e., GOT) were obtained as described pre-
viously (3); 4) anti-mouse caveolin-1 from Affinity Bioreagents
(Golden, CO); 5) anti-human 3-hydroxy-3-methylglutaryl CoA
(HMG-CoA) reductase from Upstate Cell Signaling Solutions (Lake
Placid, NY); 6) anti-human ACAT-2 from Cayman Chemical (Ann
Arbor, MI); 7) rabbit polyclonal anti-mouse glutathione S-transferase
(GST) and rabbit polyclonal anti-Pseudomonas 3?-hydroxysteroid de-
hydrogenase (3?-HSD) from USBiological (Swampscott, MA); 8)
rabbit polyclonal anti-rat organic anion transport polypeptide 1
(OATP1) from Alpha Diagnostic (San Antonio, TX); and 9) goat
polyclonal anti-mouse fatty acid translocase (FAT; CD36) from Re-
search Diagnostics (Flanders, NJ). The above primary antibodies were
detected with secondary antibodies as follows: alkaline phosphatase-
conjugate goat anti-rabbit IgG and alkaline phosphatase-conjugate
rabbit anti-goat IgG were purchased from Sigma-Aldrich. For West-
ern blot analysis, liver samples from female L-FABP?/?and
L-FABP?/?mice on control and cholesterol-rich diets were homog-
enized followed by centrifugation at 600 g for 10 min to remove
insoluble debris (21). Western blot analysis was then performed to
determine protein expression levels using the above antisera basically
as described previously (3).
Lipid analysis. The mouse liver was homogenized and fractionated,
and lipids were analyzed as described previously (2, 17). Total fatty
acid was determined utilizing the following relationship: moles of
fatty acid ? [moles of cholesterol ester ? moles of nonesterified fatty
acid ? (2 ? moles of phospholipid) ? (3 ? moles of triacylglyc-
erol)]. Quantification of total bile acid content from the mouse liver
ALTERED CHOLESTEROL DYNAMICS IN L-FABP?/?FEMALE MICE
AJP-Gastrointest Liver Physiol • VOL 290 • JANUARY 2006 • www.ajpgi.org
by the cholesterol-rich diet. This obesity-inducing effect of
L-FABP gene ablation differed somewhat from that of A-
FABP gene ablation, where increased adiposity was noted in
the cholesterol-fed, but not control-fed, A-FABP?/?mice (12).
Comparison of the current data with those of earlier studies
from this and other laboratories suggests that the obesity observed
in the present study with 13-wk-old sexually mature female
control-fed L-FABP?/?mice may be age and endocrine related
(17, 19). In future studies beyond the scope of the present
investigation, it would be of interest to examine in more detail
the role of these parameters in obesity in L-FABP?/?mice.
In summary, the present investigation contributed signifi-
cantly to our understanding of the physiological significance of
L-FABP in cholesterol metabolism in animals. These studies
with sexually mature (13 wk) female L-FABP?/?mice showed
for the first time that L-FABP gene ablation significantly
altered the response to dietary cholesterol to 1) reduce bile acid
levels, thereby reducing cholesterol elimination; 2) induce
accumulation of neutral lipid species (triacylglycerol and cho-
lesterol ester) in the liver; and 3) exacerbate body weight gain,
weight gain per kilocalorie of food consumed, and obesity. It
should be noted that these effects of dietary cholesterol and
L-FABP gene ablation were not due to alterations in food
consumption or grossly apparent differences in activity. In
addition, L-FABP gene ablation had no effect on dietary fat
absorption (19). Similarly, ablating other fatty acid binding
proteins, i.e., I-FABP (30) or SCP-2/SCP-x (26), also did not
alter food intake. In conclusion, it was shown for the first time
that L-FABP altered cholesterol metabolism and the response
of female mice to dietary cholesterol. Whereas female wild-
type L-FABP?/?mice were sensitive to dietary cholesterol,
female L-FABP?/?littermates fed a cholesterol-rich diet ex-
hibited increased hepatic cholesterol and neutral lipid (triacyl-
glycerol and cholesterol ester) accumulation. Thus studies with
gene-ablated mice demonstrate L-FABP influences not only
fatty acid metabolism (1, 8, 17, 19) but, as shown herein,
support the hypothesis that L-FABP also exhibits a physiolog-
ical role in cholesterol metabolism.
This study was supported in part by National Institutes of Health Grants
DK-41402 and GM-31651.
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