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4 Department of Physiology and Pharmacology and 5 Department of Pathobiology, Texas A&M University, Texas Veterinary Medical College, College Station, TX 77843-4467
* To whom correspondence should be addressed. E-mail: fschroeder{at}cvm.tamu.edu.
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(e.g. hepatocyte nuclear factor 1, genotype effect) and of PPAR-regulated proteins involved in uptake of free (lipoprotein lipase and fatty acid transport protein, genotype, and/or age effect) and esterified (scavenger receptor class B type 1, genotype effect) long-chain fatty acids (LCFA). Hepatic total lipid and neutral lipid levels were not affected by age or genotype, consistent with absence of gross and histologic steatosis. There was increased mRNA expression of liver proteins involved in LCFA oxidation [mitochondrial 3-oxoacyl-CoA thiolase (genotype effect) and butyryl-CoA dehydrogenase (genotype and/or age effect)], increased expression of LCFA esterification enzymes [glycerol-3-phosphate acyltransferase (age x genotype effect) and acyl-CoA:cholesterol acyltransferase-2 (genotype and/or age effect)], and increased expression of proteins involved in intracellular transfer and secretion of esterified LCFA [liver microsomal triacylglycerol transfer protein (genotype effect), serum apolipoprotein (apo) B (genotype or age effect), and liver apoB (age and age x genotype effect)]. The data support a working model in which obesity development in these mice results from shifts toward reduced energy expenditure and/or more efficient energy uptake in the gut.
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Introduction |
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Earlier in vitro studies of L-FABP function focused on structure, ligand binding characteristics, and L-FABP activity in LCFA uptake, diffusion, esterification, and oxidation, suggesting involvement (2–10) in both anabolic and catabolic LCFA pathways (review in 1). These putative functions were recently confirmed with cultured primary hepatocytes and livers from L-FABP null mice (11–16), suggesting that L-FABP may be important in regulating lipid metabolism and affecting the obese state in mice.
L-FABP also indirectly influences cellular LCFA metabolism by transporting LCFA to the nucleus for interaction with PPAR, a nuclear receptor that regulates transcription of multiple enzymes involved in LCFA uptake, transport, esterification, and oxidation (review in 17–19). Both L-FABP (review in 1,2) and PPAR (20–22) exhibit acyl chain-dependent high affinity (i.e. nmol/L Kd) for LCFA and LCFA-CoA, both of which alter conformation of these proteins. Studies in vitro and with purified nuclei (23) as well as with intact living cells (24–26) show L-FABP enhances LCFA and LCFA-CoA distribution to nuclei, directly binds PPAR, and induces PPAR transcription of LCFA oxidative enzymes. Consequently, L-FABP may regulate its own expression via PPAR (review in 27).
Previous studies in our laboratory (12) demonstrated that under conditions of stable energy intake (standard nonpurified diet), L-FABP (–/–) mice exhibit similar, but less severe, age-dependent obesity without morphologically evident hepatic steatosis as observed in PPAR null mice (28,29). To further explore the mechanistic basis of obesity in older female L-FABP (–/–) mice, the current study was undertaken to determine the age dependence of hepatic lipid distribution, serum lipid distribution, and expression of select proteins involved in LCFA metabolism. These studies provided new insights into the mechanistic basis of hepatic lipid metabolism and obesity in L-FABP gene-ablated female mice and support a working model in which the age-dependent obesity that develops in the (–/–) female mice is a result of physiological shifts in these mice toward reduced energy expenditure and/or more efficient intestinal energy uptake.
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Materials and Methods |
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, sterol regulatory element binding protein-1, caveolin-1, goat polyclonal anti-human antibodies against fatty acid transport protein-4 (FATP-4), fatty acid translocase (FAT/CD36), carnitine palmitoyltransferase I (CPT I), lipoprotein lipase (LPL), apolipoprotein (apo) B, microsomal triacylglycerol transfer protein (MTP), mitochondrial 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) synthase, hepatocyte nuclear factor-1 (HNF-1), and HNF-4, and goat polyclonal anti-mouse antibodies against LDL receptor and apoAI were from Santa Cruz Biotechnology. Rabbit polyclonal anti-human acyl-CoA:cholesterol acyltransferase-2 (ACAT-2) was from Cayman Chemical. Rabbit polyclonal anti-mouse scavenger receptor class B type 1 (SR-B1) was from Novus Biologicals. Rabbit anti-human HMG-CoA reductase was from Upstate Cell Signaling Solutions. Rabbit polyclonal anti-mouse glutathione S-transferase (GST) and anti-Pseudomonas 3-hydroxysteroid dehydrogenase (3-HSD) were from US Biological. Rabbit polyclonal anti-glycerol-3-phosphate acyltransferase (GPAT) was a generous gift of Dr. Rosalind Coleman (Department of Nutrition, University of North Carolina, Chapel Hill, NC). Alkaline phosphatase-conjugated goat anti-rabbit IgG and rabbit anti-goat IgG were from Sigma-Aldrich. All other reagents and solvents used were of the highest grade available and were cell-culture tested. Mouse studies. C57BL/6 mice were obtained from the National Cancer Institute (Frederick Cancer Research and Development Center, Frederick, MD). L-FABP gene-ablated (–/–) C57BL/6 mice were generated by targeted disruption of the L-FABP gene through homologous recombination (12) and bred to generation 6. The Animal Care and Use Committee of Texas A&M University approved all animal protocols. Mice were housed individually in ventilated microisolator cages in a temperature-controlled (25°C) facility on a constant 12-h-light/-dark cycle and were allowed to consume food and water ad libitum. All mice were fed a commercial, standard low-fat (5% of energy from fat) pelleted nonpurified diet (Supplemental Table 1; Harlan Teklad Rodent Diet 8604). The current aging study was initiated using 30 age-matched (2 mo old) (–/–) female mice. Thirty age-matched (2 mo old) (+/+) C57BL/6 female cohorts were used as controls. Every 2 d, each mouse was weighed and the amount of food consumed by each mouse was measured (14). At age 3 mo, 15 (+/+) and 15 (–/–) mice were deprived of food overnight (12 h) and anesthetized (ketamine, 100 mg/kg; xylazine, 10 mg/kg). Blood was collected by cardiac puncture and processed to serum for storage at –80°C and subsequent lipid and protein analysis. After killing the mice, livers were removed and weighed prior to further processing (14). At the end of the study (age 18 mo), the remaining (+/+) and (–/–) mice (n = 12–13/genotype) were food-deprived overnight (12 h) and killed as described above. Blood and liver were collected and processed as described above. At the time of analysis, liver (0.1–0.2 g) was minced and homogenized (motor-driven Teflon pestle) on ice in 0.4–0.5 mL of PBS (pH 7.4) with protease inhibitor cocktail.
Whole-body phenotype analysis. We analyzed whole-body phenotype longitudinally throughout the current study in mice at age 2, 3, 6, 9, and 18 mo by dual-energy X-ray absorptiometry utilizing a Lunar PIXImus densitometer to determine fat tissue mass (FTM) and bone-free lean tissue mass (LTM) according to a previously published procedure (31). Prior to PIXImus analysis, the mouse was anesthetized by an intraperitoneal injection of a mixture of ketamine and xylazine (0.01 mL/g body weight; 10 g/L ketamine and 1 g/L xylazine in 0.9% saline solution). Following the procedure, the mouse was injected with yohimbine (0.11 µg/g body weight) to facilitate recovery. The mouse was injected with warm saline solution for rehydration, kept warm during recovery with heat pads to minimize heat loss, and the mouse was checked every 30 min until recovery was complete. Determination of body composition was performed by exposing the entire mouse, minus the head region, to sequential beams of low- and high-energy X-rays with an image taken of the X-rays impacting a luminescent panel. Separation of bone mass from soft tissue mass was accomplished by measuring the ratios of signal attenuation at the different energy levels. We further separated soft tissue mass into lean and FTM to provide accurate values of body composition. Instrument calibration was performed utilizing a phantom mouse of known bone mineral density and FTM, followed by correlation to chemical extraction techniques.
Lipid analysis. Lipid, protein, and RNA data were generated from age-matched cohorts of female mice at age 3 and 18 mo. Lipids were extracted from liver homogenates (5 mg protein) and analyzed as described (12,16). We quantified serum lipids and apolipoproteins using commercially available kits: total cholesterol, Wako no. 276–64909; free cholesterol, Wako no. 274–47109; nonesterified fatty acid, Wako no. 994–75409; triacylglycerol, Wako no. 998–40391/no. 994–40491; phospholipid, Wako no. 990–54009; apoA1, Wako no. 991–27201; and apoB, Wako no. 993–27401 (Wako Diagnostics). Serum cholesteryl ester was determined by subtracting free cholesterol from total cholesterol.
Western blotting analysis. Protein expression levels in liver homogenates were measured by Western blotting of equivalent amounts of protein loaded in each lane (15,16), quantified by densitometry (14,31), and expressed in arbitrary units relative to that in 3-mo-old (+/+) mice defined as 1.0. For each Western blot, we used the following procedure to control for potential blot-to-blot variability. Aliquots of each 3-mo-old (+/+) liver homogenate containing equivalent amounts of total protein were pooled. The pooled sample was gently mixed, divided into 50-µL aliquots, and stored at –80°C for subsequent SDS-PAGE/Western blot analysis. An aliquot of the pooled 3-mo-old (+/+) homogenate that contained an amount of total protein equivalent to that of the individual liver homogenate samples to be examined by SDS-PAGE and subsequent Western blotting was removed and loaded onto each gel. After color development and densitometry, the integrated density value of the pooled 3-mo old (+/+) sample was defined as 1.0; the integrated density values of the individual liver homogenate samples on the blot of interest were normalized to this value.
Mouse liver mRNA quantification. Mouse liver mRNA levels were quantified as previously described (32). The amount of mRNA detected by RT-PCR was expressed in arbitrary units, with that present in the samples from (+/+) mice defined as 1.0.
Statistics. The current investigation used cohorts of female mice in which all (–/–) mice were of the n = 6 generation. We used repeated-measures ANOVA to analyze body weight, food intake, and fat and LTM. Tukey's post hoc test was conducted when the interaction was significant. Data from the separate groups of 3- and 18-mo-old mice were analyzed by 2-way ANOVA (genotype x age). Tukey's post hoc test was used to compare age within genotype or genotype within age when the interaction was significant (GraphPad Prism version 3.02). Data are expressed as means ± SEM. Differences with P < 0.05 were considered significant. Graphical analysis was accomplished using SigmaPlot 2002 for Windows version 8.02 (SPSS).
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Results |
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Hepatic lipid concentrations. L-FABP gene ablation significantly increased the concentration of hepatic cholesterol, cholesteryl ester, and phospholipid in female mice (Table 1). For primarily neutral storage lipids, hepatic triacylglycerol declined whereas cholesteryl ester increased in old mice (Table 1). L-FABP gene ablation did not further alter triacylglycerol concentration; however, L-FABP gene ablation resulted in an increased cholesteryl ester concentration in both young and old mice. Finally, LCFA increased with genotype or age in mice (Table 1).
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Effects of L-FABP gene ablation and aging on liver proteins of LCFA anabolic metabolism: esterification and intracellular transport for secretion of esterified LCFA. The activity of GPAT, the rate-limiting enzyme in glyceride (phospholipid, triacylglycerol) synthesis, is age and L-FABP expression dependent. L-FABP gene ablation did not affect liver GPAT concentrations in young or old mice; however, there was a significant decrease in GPAT concentration in 18-mo (+/+) mice (Table 4). Aging did not affect the expression of MTP, a protein that transports triglycerides and cholesteryl esters in cells for secretion as VLDL (Table 4). In contrast, L-FABP gene ablation increased liver MTP concentrations in young and old mice (Table 4).
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-HSD. Neither L-FABP gene ablation nor aging had any effect on GST or 3-HSD levels in mice (not shown). L-FABP gene ablation and/or aging had no effect on the level of SCP-x, a key enzyme in oxidation of the branched side chain of cholesterol to form bile acids (not shown). HMG-CoA synthase is involved in de novo synthesis of cholesterol (precursor of cholesteryl ester), but expression of this protein was not affected by age or L-FABP ablation (not shown). Age and/or L-FABP gene ablation also did not alter HMG-CoA reductase levels in females (not shown).
Effects of L-FABP gene ablation and aging on liver proteins important for LCFA catabolic metabolism: mitochondrial and peroxisomal oxidation. CPT I, a rate-limiting enzyme in mitochondrial LCFA oxidation, increased with age or L-FABP gene ablation in mice (Table 4). L-FABP gene ablation resulted in increased hepatic levels of mitochondrial 3-oxoacyl-CoA thiolase mRNA in 3- and 18-mo-old mice (Table 4). Butyryl-CoA dehydrogenase mRNA concentration significantly increased in older mice regardless of genotype (Table 4).
Effects of L-FABP gene ablation and aging on key nuclear receptors of LCFA and cholesterol metabolism.
We examined the expression of certain key nuclear receptors involved in regulating transcription of enzymes/proteins participating in LCFA uptake, transport, esterification, and oxidation. Neither L-FABP gene ablation nor aging affected levels of the active 68-kDa nuclear form of sterol regulatory element binding protein-1 involved in cholesterol and fatty acid metabolism (not shown). PPAR, which regulates expression of proteins participating in LCFA transport into the cell, LCFA oxidation, and glucose metabolism, was increased by age regardless of genotype (Table 4). HNF1 and HNF4 regulate expression of multiple proteins in LCFA metabolism, including PPAR. HNF1 expression was increased by L-FABP gene ablation in young mice (Table 4), but levels of HNF4 were not affected in either young or old mice (not shown).
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Discussion |
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in nuclei (25,26), and regulation of PPAR transcriptional activity of genes involved in LCFA uptake, oxidation, lipoprotein transport, and glucose metabolism (17,24–26). If, as suggested by in vitro and cultured cell studies, L-FABP contributes significantly to physiological regulation of PPAR, then L-FABP null mice should exhibit phenotypic similarities to PPAR null mice, which show age-dependent obesity without hepatic steatosis but with increased serum triacylglycerols (28,33). L-FABP (–/–) female male mice exhibit age-dependent obesity without hepatic steatosis, in a phenotype similar to, but less severe than, that observed in PPAR null mice (28,33). The data presented herein yielded several mechanistic insights into age-dependent obesity in L-FABP null mice.
First, obesity in older (–/–) mice was associated with select elevation in serum triacylglycerol and cholesterol and serum apoB, whereas serum cholesteryl ester decreased. This pattern of lipid and apo changes was consistent with, but does not prove, increased VLDL (review in 34,35) similar to that observed in older PPAR (–/–) female mice (28), suggesting that changes in L-FABP may regulate PPAR-related pathways.
Second, obesity in older (–/–) mice was associated with selective increases in liver cholesterol, cholesteryl ester, and phospholipid (but not triacylglycerol) as well as apoB. In contrast, older PPAR (–/–) female mice had not only higher liver cholesterol but also higher cholesteryl ester and triacylglycerol (28). These chemical analyses were consistent with lack of morphological evidence of overt steatosis in livers of older (–/–) female mice. Although steatosis was also not morphologically evident in livers of older PPAR (–/–) female mice, chemical analysis indicated that older female PPAR (–/–) mice exhibited increased liver lipid levels compared with older L-FABP (–/–) female mice, consistent with the fact that L-FABP is only one (26) of several proteins (review in 17–19) that activate PPAR transcriptional activity. The absence of overt steatosis in PPAR (–/–) female mice and in L-FABP (–/–) females suggests more efficient packaging and export of lipids from the livers of these mice.
Third, as shown by Western blotting and/or RT-PCR, the age-dependent lipid changes observed prominently in old obese (–/–) female mice were associated with increased expression of select liver proteins LPL and FATP involved in LCFA tissue release/uptake. The increased hepatic level of LPL is especially significant in view of LPL not being synthesized in liver, but rather in adipose and muscle tissue from where it must be transported to endothelial cells in liver as well as adipose, muscle, and other tissues. The finding of increased LPL and FATP in older obese L-FABP (–/–) females indicates increased LCFA hepatic uptake and suggests, but does not prove, an increased level of LPL in adipose tissue that could contribute to the adiposity noted in older obese (–/–) mice. Whether these proteins are elevated in older obese PPAR (–/–) females is not known.
Fourth, obesity in older (–/–) mice was associated with increased LCFA esterification (ACAT-2) and intracellular transfer/secretion of esterified LCFA (MTP, apoB). Interestingly, coordinate repression of MTP (MTP inhibitor 8aR) and L-FABP (gene ablation) in standard nonpurified diet-fed young mice resulted in decreased VLDL secretion without hepatosteatosis (36). However, L-FABP gene ablation alone increased MTP expression in female mice.
The age-dependent obesity in L-FABP (–/–) mice was unique compared with that of other known FABP-targeted mice, including adipocyte FABP (–/–) mice, which exhibited increased body weight gain compared with their wild-type counterparts only when fed a high-fat diet (37); intestinal FABP (–/–) mice, which displayed no differences in body weight gain when fed either a control diet or a high-fat, high-cholesterol diet compared with their wild-type counterparts (38); and epidermal FABP (–/–) mice, which were phenotypically normal (39).
Ultimately, the increased body weight and FTM observed in L-FABP (–/–) female mice must be due to an energy imbalance in these mice. This energy imbalance can arise from increased food intake, change in metabolic rate, and/or differences in feed efficiency. Although (+/+) and (–/–) mice did not differ in food intake or physical activity, these conclusions were based on subjective observations and need to be examined in more detail.
In summary, the net effect of the lipid and protein changes in older obese (–/–) mice was to shift the balance of hepatic LCFA metabolism toward a net increase in LCFA uptake (LPL, FATP), esterification (ACAT-2, GPAT), transport/secretion as VLDL (MTP, apoB), and utilization by adipose tissue for storage. This phenotype shared many, but not all, attributes with those reported for PPAR (–/–) mice, supporting the view that L-FABP and PPAR influence some common pathways that regulate lipid metabolism. The data reported herein support a working model in which loss of L-FABP results in obesity without obvious steatosis. The absence of steatosis could result from more efficient packaging and export of lipids from the liver. Because food consumption was equivalent in wild-type and L-FABP gene-ablated mice, obesity development in the knockout mice must have resulted from shifts toward a reduced energy expenditure and/or more efficient energy uptake in the gut.
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FOOTNOTES |
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2 Author disclosures: G. G. Martin, B. P. Atshaves, A. L. McIntosh, J. T. Mackie, A. B. Kier, and F. Schroeder, no conflicts of interest.
3 Supplemental Table 1 is available with the online posting of this paper at jn.nutrition.org.
6 Abbreviations used: ACAT-2, acyl-CoA:cholesterol acyltransferase-2; apo, apolipoprotein; CPT I, carnitine palmitoyl transferase I; FABP, fatty acid-binding protein; FAT/CD36, fatty acid translocase; FATP-4, fatty acid transport protein-4; FTM, fat tissue mass; GPAT, glycerol-3-phosphate acyltransferase; GST, glutathione S-transferase; HMG-CoA, 3-hydroxy-3-methylglutaryl CoA; HNF, hepatocyte nuclear factor; 3-HSD, 3-hydroxysteroid dehydrogenase; LCFA, long-chain fatty acid; L-FABP, liver FABP; LPL, lipoprotein lipase; LTM, lean tissue mass; MTP, microsomal triacylglyerol transfer protein; SCP-2, sterol carrier protein-2; SCP-x, sterol carrier protein-x/3-ketoacyl-CoA thiolase; SR-B1, scavenger receptor class B type 1; TTM, total tissue mass; (+/+), liver fatty acid binding protein wild-type mice; (–/–), liver fatty acid binding protein gene-ablated mice.
Manuscript received 30 January 2008. Initial review completed 27 March 2008. Revision accepted 23 July 2008.
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