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Endocrinology Vol. 145, No. 4 1842-1848
Copyright © 2004 by The Endocrine Society

Estrogen Replacement Reverses the Hepatic Steatosis Phenotype in the Male Aromatase Knockout Mouse

Kylie N. Hewitt, Kyriakos Pratis, Margaret E. E. Jones and Evan R. Simpson

Prince Henry’s Institute of Medical Research (K.N.H., K.P., M.E.E.J., E.R.S.), Clayton, Victoria 3168, Australia; and Department of Biochemistry and Molecular Biology (K.N.H., E.R.S.), Monash University, Clayton, Victoria 3800, Australia

Address all correspondence and requests for reprints to: Kylie Hewitt, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: kylie.hewitt{at}phimr.monash.edu.au.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to a disruption to the Cyp19 gene. Previously we have shown both male and female ArKO mice have an age progressive obese phenotype and a sexually dimorphic disruption to hepatic cholesterol and triglyceride homeostasis. Only ArKO males have elevated hepatic triglyceride levels leading to hepatic steatosis partly due to an increase in expression of enzymes involved in de novo lipogenesis and transporters involved in fatty acid uptake. In this study ArKO males were treated with 17ß-estradiol (3 µg/ kg·d) at 18 wk old for 6 wk. Wild-type controls were not treated, and ArKO controls received vehicle oil injections. Estrogen replacement reverses the previously reported obese and fatty liver phenotypes; this was achieved by reductions in gonadal, visceral, and brown adipose tissue weights and significantly decreased hepatic triglyceride levels. Estrogen deficiency led to a significant up-regulation of hepatic fatty acid synthase expression, which was reduced with 17ß-estradiol replacement, although not quite reaching significance. Acetyl Coenzyme A carboxylase {alpha} mRNA expression showed no significant changes. Expression of transcripts encoding adipocyte differentiated regulatory protein, a fatty acid transporter, was significantly elevated in estrogen-deficient males, and 17ß-estradiol replacement significantly reduced these levels. Scavenger receptor class b type 1 showed no significantly changes. This study reveals that the previously reported disruption to triglyceride homeostasis in estrogen-deficient males can be reversed with 17ß-estradiol treatment, indicating an important role for estrogen in maintaining triglyceride and fatty acid homeostasis in males.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HEPATIC STEATOSIS IS linked to insulin resistance (IR) and metabolic syndrome (1, 2). Features of metabolic syndrome include central obesity rather than peripheral obesity, dyslipidemia, characterized by elevated triglycerides, low-density lipoproteins, and reduced high-density lipoproteins (3). Menopausal women have a reduction in circulating estrogen levels and this coincides with a shift in body fat from the gluteal to the abdominal region, thus linking lack of estrogen to central obesity (3). In addition to this shift in body fat, postmenopausal women have elevated circulating triglyceride levels, compared with premenopausal women, and men in general are also known to have higher circulating levels of triglycerides, compared with women, again establishing a strong relationship between estrogen and triglyceride levels.

Mouse models of estrogen deficiency also present with dyslipidemia. Specifically, the aromatase knockout (ArKO) mouse (4) presents with central obesity, hypercholesterolemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia (5), and importantly the male mice have hepatic steatosis (Ref. 5 and Hewitt, K. N., W. C. Boon, Y. Murata, M. E. Jones, and E. R. Simpson, submitted manuscript). Estrogen receptor (ER) {alpha}-knockout ({alpha}ERKO) mice and the ER{alpha} and -ß double-knockout ({alpha}ßERKO) mice (6, 7) also display an obese phenotype similar to the ArKO mice (5), but the hepatic phenotype of these animals has not been reported. The ERß-knockout (ßERKO) mouse does not have a lipid phenotype (7), thereby suggesting ER{alpha} is the more important ER in terms of lipid homeostasis.

We have reported that the hepatic steatosis present in ArKO males is due to an accumulation of hepatic triglycerides. Molecular characterization of this phenotype revealed that estrogen deficiency in males led to elevated fatty acid synthase (FAS) and acetyl CoA carboxylase {alpha} (ACC{alpha}) expression. There was also an increase in expression of adipocyte differentiated related protein (ADRP), a fatty acid transporter present in the liver (Hewitt, K. N., W. C. Boon, Y. Murata, M. E. Jones, and E. R. Simpson, submitted manuscript). There was no change in apolipoprotein E expression, suggesting there was no compensatory increase in very low-density lipoprotein secretion, which would allow an increase in hepatic triglyceride clearance, thus further exacerbating the phenotype (Hewitt, K. N., W. C. Boon, Y. Murata, M. E. Jones, and E. R. Simpson, submitted manuscript). Additionally, we failed to observe an increase in fatty acid ß-oxidation. As well as elevated hepatic triglycerides in estrogen-deficient male mice, previously we have reported that male ArKO mice also have elevated levels of hepatic cholesterol (8). In addition to our model, Toda et al. (9) generated another ArKO mouse model by disrupting exon 9 of the Cyp19 gene. They reported the presence of hepatic steatosis due to a disruption in ß-oxidation, shown at the level of gene expression as well as the catalytic activity of these enzymes. This phenotype was reversed by 17ß-estradiol treatment (10); however, they did not indicate whether this was sexually dimorphic.

Human models of aromatase deficiency have also been identified (11, 12, 13, 14, 15), and, like the ArKO mouse, they also present with dyslipidemia. In one male patient, hepatic steatosis that was reversed with 17ß-estradiol treatment was described (14).

Therefore, the aim of this present study was to attempt to rescue the fatty liver phenotype in the male ArKO mouse with 17ß-estradiol treatment.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice
The ArKO mice were generated by deleting 90% of exon 9 of the Cyp19 gene as described by Fisher et al. (4). Wild-type (WT) and homozygous null offspring were generated by heterozygous matings. The genotype of the offspring was determined by PCR as described by Robertson et al. (16). The animals were housed in specific pathogen-free conditions and had unlimited access to drinking water and food. These studies were approved by the Monash Medical Centre Animal Ethics Committee.

Diets
Soy-free mouse chow (Glen Forest stock feeders, Perth, Australia) is the diet used to feed the mice; it contains no soy products, which are found in regular mouse chow, because soy is known to have estrogenic effects (17). This diet contains 15% of calories as fat (0.02% cholesterol), 20% calories as protein, and 65% of calories as carbohydrate.

Hormone preparation
17ß-estradiol (E2) (Sigma, St Louis, MO) was dissolved in methylene chloride (Unilab, Ackland, New Zealand) and added to peanut oil (methylene chloride/oil, 1:2 vol/vol). The methylene chloride was evaporated by bubbling with nitrogen and warming the solution to 37 C. Vehicle oil injections were identically prepared, omitting E2.

Experimental design
ArKO males received daily sc injections of E2 (3 µg/ kg·d) from 18 wk of age for 6 wk. WT controls did not receive any treatment and ArKO controls received vehicle oil injections.

Tissue collection and histology
Animals were weighed and then killed at 24 wk of age by CO2 asphyxiation. Blood was removed by cardiac puncture and stored at -20 C. The liver was removed, weighed, and part of it snap frozen in liquid nitrogen and stored at -80 C for gene and lipid analysis. Part of the liver was immersion fixed in Bouin’s fixative then stored in 70% ethanol. Fixed samples were embedded in a random orientation in paraffin and sliced into 7-µm sections. Sections were then stained with hematoxylin, counterstained with eosin, and coverslipped with DPX (BDH, Poole, UK). Gonadal, visceral, and brown adipose tissue (BAT) pad were also removed and weighed.

Measurement of hepatic triglycerides and cholesterol
Hepatic triglycerides and cholesterol were extracted from liver by homogenizing 0.2 g of tissue in 10 ml chloroform/methanol (2:1 vol/vol) (18). Samples were centrifuged for 20 min at 800 g, the lipid phase removed, and the chloroform evaporated. Triglyceride and cholesterol were quantified using Infinity triglyceride lipid stable reagent (Thermo Trace, Melbourne, Australia) and cholesterol lipid incorporating dynamic stabilization technology (Thermo Trace), respectively. Triglyceride and cholesterol calibrators were used as references (Sigma).

Gene analysis
RNA was extracted from liver using the phenol-chloroform method (Ultraspec RNA, Fisher Biotech, Australia) and quantified spectrophotometrically. RNA quality was assessed on an ethidium bromide (Sigma) agarose (Promega Life Sciences, Madison, WI) gel. Two-step RT-PCR was performed using random primers (Roche, Mannheim, Germany) and AMV reverse transcriptase enzyme (Promega). A Lightcycler (Roche) was used to quantitate mouse transcripts using specific primer pairs (Table 1Go). Primer pairs were shown to be specific through single peak melting curves, and a single product was seen on an ethidium bromide (Sigma) agarose (Promega) gel corresponding to the appropriate product size as measured by a 1-kb ladder (Promega). All products were sequenced to confirm identity.


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  		TABLE 1. Primer sequences, product size, and PCR conditions

 
All samples were normalized to 18S because the mRNA expression was not altered by estrogen status. All samples were run individually in three separate reverse transcription reactions and transcripts measured using real-time PCR. The data were presented as the mean of three consistent runs. Interassay variability was assessed using reference cDNA from a control animal in repeated runs.

Statistical analysis
All graphs were expressed as means ± SEM, and statistics were performed using ANOVA (SPSS for Windows, version 10.0, Chicago, IL). A minimum of five animals were used per group.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Body weight
Although ArKO male mice were slightly heavier weight than the WT control mice, this did not reach statistical significance. However, after E2 replacement, the body weight of the ArKO mice returned to the weight of the WT control mice (P = 0.002, Fig. 1AGo).



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  		FIG. 1. Organ weight data. A, Body weight. There was no significant difference in WT and ArKO mice, and E2 replacement significantly reduced body weight in ArKO mice (*, P < 0.05). B, Liver weight. ArKO mice have significantly elevated liver weight, compared with WT mice (*, P < 0.05), which is significantly reduced with E2 replacement (*, P < 0.05). C, Gonadal fat pad weight. ArKO mice have significantly heavier fat pad weight, compared with WT mice (*, P < 0.05). No significant change is seen with E2 replacement. D, Visceral fat pad weight. ArKO mice were significantly heavier than WT; E2 replacement significantly reduced this (*, P < 0.05). E, BAT, No significant differences were seen between controls, and E2 replacement significantly reduced BAT weight (*, P < 0.05). ArKO (KO), white bars; WT, black bars; E2 estrogen replacement, number in brackets refers to animals per group.

 
Liver weight
Control ArKO mice had a significantly heavier liver weight, compared with WT control mice (P = 0.026, Fig. 1BGo). E2 led to a reduction in ArKO liver weight to levels comparable with WT controls (P = 0.003, Fig. 1BGo).

Fat pad weight data
ArKO male control mice had significantly heavier gonadal fat pad weight, compared with WT control mice (P = 0.038, Fig. 1CGo). E2 replacement did not significantly reduce gonadal fat pad weight in the ArKO mice (P = 0.111, Fig. 1CGo).

ArKO control mice also had significantly heavier visceral fat pad weight, compared with WT control mice (P = 0.027, Fig. 1DGo), and E2 treatment significantly reduced visceral fat pad weight in the treated ArKO mice (P = 0.04, Fig. 1DGo).

There were no significant differences between ArKO and WT male mice in BAT weight (P = 0.098, Fig. 1EGo), although there was an apparent increase in weight in the ArKO mice; however, E2 replacement in the ArKO mice led to a significant reduction in BAT weight, compared with ArKO control mice (P = 0.008, Fig. 1EGo).

Liver morphology
ArKO male mice have an accumulation of lipids in their livers (Fig. 2BGo), which are not apparent in the WT male mice (Fig. 2AGo). After E2 replacement there was a reversal of the fatty liver phenotype (Fig. 2CGo).



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  		FIG. 2. Liver morphology. A, WT mice have no lipid droplet. B, ArKO mice have lipid droplets. C, ArKO mice with E2 replacement reduced lipid droplets, compared with control ArKOs. Scale bar, 100 µm.

 
Hepatic triglyceride and cholesterol levels
ArKO control mice had significantly increased levels of hepatic triglyceride levels, compared with WT controls (P = 0.000, Fig. 3AGo). These levels were significantly reduced with E2 treatment (P = 0.000, Fig. 3AGo).



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  		FIG. 3. Hepatic lipid levels. A, Hepatic triglyceride levels. ArKO levels were significantly higher, compared with WT (P < 0.05), and E2 replacement significantly reduced these levels (*, P < 0.05). B, Hepatic cholesterol levels. ArKO levels were significantly higher, compared with WT (P < 0.05). There was no significant change with E2 replacement. ArKO (KO), white bars, WT, black bars, E2 estrogen replacement.

 
ArKO control mice had significantly elevated hepatic cholesterol levels, compared with WT control mice, (P = 0.003, Fig. 3BGo); however, E2 replacement in the ArKO mice did not significantly affect these levels (P = 0.558, Fig. 3BGo).

Expression of transcripts encoding enzymes involved in de novo synthesis of fatty acids
To explain the changes in body, fat, and liver weight, hepatic triglyceride levels after E2 replacement, liver samples were analyzed for expression of various genes, which have previously been shown to the altered in ArKO male mice.

ArKO control mice showed a significant up-regulation of FAS expression, compared with WT mice (P = 0.004). With E2 treatment there was a decrease in FAS expression in the ArKO mice (P = 0.096, Fig. 4AGo), although this did not reach significance.



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  		FIG. 4. Gene expression data. A, FAS expression. ArKO levels were significantly higher, compared with WT (*, P < 0.05). B, ACC{alpha}. No significant changes. C, ADRP expression. ArKOs levels were significantly elevated, compared with WT (*, P < 0.05). E2 treatment significantly reduced expression in ArKOs (*, P < 0.05). D, Scavenger receptor class b type 1 expression with no significant changes. ArKO (KO), white bars; WT, black bars, E2 estrogen replacement.

 
ACC{alpha}, another key enzyme involved in de novo synthesis of fatty acids, showed similar changes; however, these did not reach the level of significance among any of the groups measured (Fig. 4BGo).

Gene expression of fatty acids transporters
ADRP, a fatty acid transporter, was significantly up-regulated in the ArKO male mice, compared with WT control mice (P = 0.005); additionally, there was also a significant decrease in its expression after the E2 replacement in ArKO mice (P = 0.003, Fig. 4CGo).

Scavenger receptor class b type 1 is also involved in uptake of fatty acids and cholesterol uptake but showed no significant differences among any of the groups (Fig. 4DGo).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have previously shown that estrogen deficiency in male mice leads to hepatic steatosis (Ref. 5 and Hewitt, K. N., W. C. Boon, Y. Murata, M. E. Jones, and E. R. Simpson, submitted manuscript). In the present study, we demonstrate that this phenotype can be rescued by E2 replacement. This treatment significantly reduced hepatic triglycerides, with a concomitant decrease in lipid droplets; conversely, E2 replacement had little effect on hepatic cholesterol levels. Additionally, estrogen deficiency led to an increase in transcripts encoding factors involved in lipogenesis and long-chain fatty acid uptake in the male mice, and the levels of these transcripts were normalized by E2 replacement. Not only did the E2 replacement have positive effects on the liver, but it also reduced the body weight, visceral pad weight, BAT weight, and a trend for a reduction in gonadal fat pad weight, indicating a general effect of E2 to reduce lipid accumulation. The results are summarized in Table 2Go.


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  		TABLE 2. Summary of results

 
There is an increasing body of evidence to suggest that there is a link between hepatic steatosis, IR, and obesity (2, 19). A key defect in IR is central adipose tissue resistance to insulin-mediated suppression of lipolysis (20). A consequence of this resistance is elevated free fatty acid (FFA) levels (20). FFAs from central adipose depots are able to drain directly into the portal blood and promote hepatic gluconeogenesis, which increases hepatic glucose output (2, 20), stimulating the pancreatic ß-cells to increase insulin secretion, which up-regulates lipogenesis in the liver (20). Insulin also acts to inhibit lipolysis; however, when there is central obesity, these actions are impaired. Thus, a positive loop of dysregulated lipid homeostasis is generated, eventuating in hepatic steatosis.

Estrogen deficiency in male mice leads to hepatic steatosis, probably due in part to an increase in lipogenesis indicated by increases in FAS and ACC{alpha} expression; E2 replacement lowered the expression of FAS. Despite these findings, other studies have shown estrogen to be a stimulator of lipogenesis in chick livers (21, 22), the rat liver (23), and male Xenopus laevis (24), although in ewes E2 treatment inhibited lipogenesis (25). This was, however, in adipose tissue rather than in the liver.

Long-chain fatty acid uptake may also be elevated in the state of estrogen deficiency as seen by increased levels of ADRP expression. This is reversed with E2 replacement. The mechanism whereby estrogen regulates ADRP expression is not yet understood; nevertheless, another transporter, FAT/CD36, is also affected by sex steroids (26). These studies reveal a possible involvement of estrogen in the regulation of FFA transport.

Adipose tissue is believed to have a buffering action by suppressing the release of FFAs into the circulation and increasing triglyceride clearance (27). In the circumstance of obesity, adipose tissue function is altered so that buffering is less effective and the adipocytes are filled, hence resisting further fat storage (27). Conversely, rodents who have lipodystrophy also present with IR and diabetes (28, 29, 30). This lack of adipose tissue prevents any buffering of FFAs, also contributing to the accumulation of triglycerides in the liver as well as skeletal muscle and pancreas (29, 31). Previously we have established that in the state of estrogen deficiency in both males and females, obesity is associated with an increased adipocyte volume (5) and estrogen replacement reverses the obese phenotype by causing a decrease in adipocyte volume, whereas there was very little change in adipocyte number (5, 32). The present study demonstrated that E2 replacement in males decreases obesity by reducing gonadal, visceral, and BAT adipose depots. It is possible that the large adipocyte volumes observed in the estrogen-deficient mice (5, 32) are unable to buffer the effects of FFAs; therefore, the liver, another important site of triglyceride buffering (33), stores trigylcerides as a means of protecting other sites within the body. E2 acts on the adipose depots to reduce their size and hence obviate the need for the liver to assist in the buffering of triglycerides.

The presence of central obesity is not necessarily a predictor of hepatic steatosis; as shown in estrogen-deficient males and females, both are obese but only the males present with hepatic steatosis. In this case centrally mediated factors may be playing an important role; estrogen-deficient males show loss of neurones in the arcuate nucleus and medial preoptic area regions of the hypothalamus (Hill, R., M. E. Jones, S. Pompolo, E. R. Simpson, and W. C. Boon, submitted manuscript). The arcuate nucleus and medial eminence regions contain the highest concentration of leptin receptors in the brain (34). Leptin is a peptide hormone that is secreted from adipose tissue, which acts in a feedback fashion on its receptors that are present in the hypothalamus. Its functions are to regulate food intake and spontaneous physical activity (1), and more recently it has been shown to inhibit lipogenesis and cholesterol synthesis and stimulate fatty acid oxidation (1, 34). Leptin-deficient models present with hepatic steatosis; hence, there may be a reduction in leptin signaling in the ArKO males, which is due to damage to the hypothalamus that is contributing to the hepatic steatosis.

GH secretion is also centrally mediated, and GH-deficient patients have also presented with hepatic steatosis (35, 36), and reversal has been shown in one patient on GH replacement (36). GH is known to act on liver to regulate the expression of certain cytochrome P450 isoforms in a sexually dimorphic fashion (37, 38). Whether its action extends to triglyceride balance remains to be determined.

Previously we reported that estrogen deficiency in males resulted in elevated hepatic cholesterol levels, which were further increased by a high-cholesterol diet (8). This present study has shown that although estrogen deficiency led to elevated hepatic cholesterol levels, E2 replacement in the males did not reverse this phenotype. Thus, hepatic cholesterol levels may be regulated independently of obesity.

The emergence of estrogen as an important regulator of lipid homeostasis is becoming increasingly clear. This present study adds further weight to this concept and highlights the role of estrogen in regulating lipid homeostasis in males, particularly hepatic triglyceride homeostasis.


   Footnotes
 
This work was supported by U.S. Public Health Service Grant R37AG08174.

Abbreviations: ACC{alpha}, Acetyl CoA carboxylase {alpha}; ADRP, adipocyte differentiated related protein; ArKO, aromatase knockout; BAT, brown adipose tissue; E2, 17ß-estradiol; ER, estrogen receptor; ERKO, ER knockout; FAS, fatty acid synthase; FFA, free fatty acid; IR, insulin resistance; WT, wild-type.

Received October 14, 2003.

Accepted for publication December 8, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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