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© 2008 American Society for Nutrition J. Nutr. 138:497-501, March 2008

Nutrition and Disease

Mammalian Sirtuin 1 Is Involved in the Protective Action of Dietary Saturated Fat against Alcoholic Fatty Liver in Mice1,2

Min You3,*, Qi Cao3, Xiaomei Liang3, Joanne M. Ajmo3 and Gene C. Ness4

3 Departments of Molecular Pharmacology and Physiology and 4 Molecular Medicine, University of South Florida Health Sciences Center, Tampa, FL 33612

* To whom correspondence should be addressed. E-mail: myou{at}health.usf.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
This study was undertaken to elucidate the mechanism underling the protective effect of a high saturated fat (HSF) diet against the development of alcoholic fatty liver in mice. We tested the effects of a HSF diet on the ethanol-mediated increase in hepatic sterol regulatory element binding protein 1 (SREBP-1) activity. Thirty-two male mice were divided into 4 groups and fed liquid diets consisting of either a high polyunsaturated fat (40% of energy from corn oil) or a HSF (40% of energy from cocoa butter) diet with or without ethanol for 4 wk. In the ethanol-containing diets, ethanol was substituted for an equivalent amount of carbohydrate to provide 27.5% of the total energy. Control mice were pair-fed the same volume of liquid diets as the ethanol-fed mice. The HSF diet suppressed the increase in mature SREBP-1 protein and prevented increased mRNA of the SREBP-1-regulated lipogenic enzymes in the ethanol-fed mice (P < 0.05). Sirtuins 1 (SIRT1), a NAD+-dependent class III histone deacetylase, was upregulated by ethanol administration in mice fed the HSF diet (P < 0.05). The HSF diet blocked histone H3 at lysine 9 (lys9) hyperacetylation and attenuated association of acetylated histone H3-Lys9 with the promoters of mitochondrial glycerol-3-phosphate acyltransferase and stearoyl-CoA desaturase 1 in the livers of the ethanol-fed mice. These results suggest that the protective effects of HSF diet against the development of alcoholic liver steatosis may occur via regulation of the hepatic SIRT1-SREBP-1-histone H3 axis, suppressing the expression of genes encoding lipogenic enzymes and slowing the synthesis of hepatic fatty acids.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Accumulation of fat in the liver is a crucial first step in the pathogenesis of alcoholic liver disease. However, its molecular mechanism remains incompletely understood. Understanding the underlying mechanisms could be the key to providing new therapeutic strategies for early intervention and treatment of alcoholic liver disease. Accumulating evidence has demonstrated that chronic ethanol administration, by increasing levels of mature, nuclear hepatic sterol regulatory element binding protein 1 (SREBP-1)5 and its targeted transcripts, acetyl-CoA carboxylase, fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), ATP citrate lyase, and mitochondrial glycerol-3-phosphate acyltransferase (GPAT1), can lead to increased fatty acid synthesis and triglyceride accumulation in animal liver (1–9).

Evidence of post-transcriptional modulation of SREBP-1 by reversible acetylation has been accumulating (10–13). CBP/p300, a histone acetyltransferase (HAT), promotes SREBP-1 DNA-binding activity by acetylating lysine residues (10). The acetylated lysine residues of SREBP-1 are also targets of ubiquitination. Thus, acetylation inhibits proteasome-mediated degradation of activated SREBP-1 (10).

Mammalian sirtuins 1 (SIRT1) is a NAD+-dependent class III histone deacetylase (HDAC) (14). Considerable evidence suggests that SIRT1 functions as a master metabolic regulator by either directly modifying histones or by indirectly regulating the activities of several transcriptional regulators (15–21). A potential link between SIRT1 and SREBP-1 has been suggested (15). SIRT1 may deacetylate SREBP-1, thus inhibiting SREBP-1 activity.

Several lines of evidence have shown that a diet high in SFA or medium chain triglycerides prevents the development of alcoholic fatty liver in animals (22–28). We previously demonstrated that saturated fat may protect against alcoholic liver steatosis by increasing circulating adipose-derived adiponectin in mice (29). Increased adiponectin signaling enables the liver to stimulate AMP-activated kinase (AMPK), a key "metabolic switch" controlling lipid metabolism. Activation of AMPK by adiponectin in the liver leads to increased hepatic fatty acid oxidation, thereby preventing hepatic lipid accumulation in ethanol-fed mice (29). However, an unsolved question was whether saturated fat reverses increased expression and processing of hepatic SREBP-1c in mice in response to chronic ethanol exposure. In this study, we examined the effects of a diet high in SFA on ethanol-induced hepatic SREBP-1 processing in mice and explored the potential role of SIRT1 in the protective action of dietary saturated fat against alcoholic liver steatosis.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Reagents. Most chemicals and supplies were purchased from Sigma Chemical, Schleicher and Schuell, GIBCO BRL, and Dupont NEN Research Products. Ethanol was purchased from Aldrich. N-acetyl-leucinal-leucinal-norleucinal (ALLN) was purchased from Calbiochem.

    Animals and diets. The detailed animal feeding protocol and diet composition were described previously (1,3,29). Liquid diets were based upon the modified Lieber-DeCarli formulation (30). Protein content was constant at 18% of total energy and each diet had identical mineral and vitamin content and contained safflower oil (4% of energy) to provide essential fatty acids. In brief, male C57BL/6J mice (6–8 wk old) were divided into 4 diet groups: 1) high polyunsaturated fat (HPF; no. 710319, prepared by Dytes) (40% of energy from fat, primarily from corn oil); 2) ethanol-containing HPF (HPF+E) [identical to the control HPF diet except with ethanol added to account for 27.5% of total energy and the energy equivalent of carbohydrate (maltose-dextrin) removed]; 3) high saturated fat [HSF; no. 710318, prepared by Dytes, 40% of energy from fat, primarily from cocoa butter]; and 4) ethanol-containing HSF [HSF+E; identical to the control HSF diet except with ethanol added to account for 27.5% of total energy and the energy equivalent of carbohydrate (maltose-dextrin) removed]. Control mice were pair-fed the same volume of liquid diets as given to ethanol-fed mice to ensure that all mice consumed the same amount of energy for 4 wk. After 4 wk of pair-feeding, the liquid diets were withdrawn ~5 h before the mice were killed by exposure to carbon dioxide in a gas chamber. The protocols for these animal studies were approved by the Institutional Animal Care Use Committees of Indiana University School of Medicine and University of South Florida. Ethanol feeding for 4 wk had no apparent effect on the health status of the animals (29). While feeding mice ethanol and a HPF liquid diet led to accumulation of lipid in the liver, the development of hepatic steatosis was alleviated when the same amount of ethanol was administered to mice consuming a HSF diet (29). We have reported previously the relevant hepatic histology and lipid data in these mice (29).

    Preparation of liver nuclear extracts. Liver nuclear proteins were extracted using the nuclear extract kit (Active Motif) according to the manufacturer's protocol. Protease inhibitor (2%) (Roche Diagnostics) and 25 mg/L ALLN were included in the procedures.

    Acetylation of PPAR{gamma} coactivator 1{alpha} and nuclear SREBP-1. PPAR{gamma} coactivator 1 (PGC-1{alpha}) or nuclear SREBP-1 protein was immunoprecipitated from mouse liver nuclear extracts using anti-PGC-1{alpha} or anti-SREBP-1 antibody (Santa Cruz) (16). PGC-1{alpha} or nuclear SREBP-1 levels and acetylation were detected using specific antibodies for PGC-1{alpha} or SREBP-1 and acetyl-lysine (Cell Signaling). For nuclear SREBP-1 measurements, 50 mg/L ALLN was included in the procedures.

    Immunoprecipitation and Western blots. For immunoprecipitation, primary antibodies were mixed with precleared lysates and 20 µL protein agarose A/G (Santa Cruz). The reactions were tumbled overnight at 4°C. The agarose beads were washed; the protein was eluted and then subjected to Western blotting analysis. Protein was detected on Western blots and levels were quantified by a PhosphorImager. Polyclonal histone H3, acetylated histone H3-lys9, and SIRT1 antibodies were purchased from Upstate Biotechnology.

    RT and RT-PCR. Liver total RNA was prepared as described (29). RT of total RNA to cDNA was performed using the StrataScript QPCR cDNA Synthesis kit (Stratagene). RT-PCR amplification was performed in a MX4000 Spectrofluorometric thermal cycler (Stratagene) using a Brilliant SYBR Green QPCR Master Mix (Stratagene). Primer sets optimized for the tested targets for SYBR Green based RT PCR, including SIRT1, GPAT1, SCD1, FAS, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), or β-actin, were purchased from Superarray, Bioscience Corporation. The relative amount of target mRNA was calculated using the comparative threshold (Ct) method by normalizing target mRNA Ct to those for GAPDH or β-actin ({Delta}Ct).

    HDAC and HAT enzyme activity assay. The activity of HDAC was measured with the use of a nonisotopic assay that used a fluorescent derivative of epsilon-acetyl lysine in the absence of NAD+ (AK-500, HDAC Fluorescent Activity Assay kit, Biomol). HAT activity was determined by a nonradioactive ELISA HAT assay kit that measured the incorporation of acetyl-CoA to a histone H3 peptide (K332, HAT Activity Assay kit, Upstate Biotechnology).

    Chromatin immunoprecipitation assay and RT-quantitative PCR (in liver). Chromatin immunoprecipitation (ChIP) assays were performed as described (31). In brief, liver tissue was fixed with 1% formaldehyde. The chromatin was sonicated to generate fragments. ChIP assays were carried out using ChIP-qualified antibody against acetyl-histone H3-lys9 (07–352, Upstate Biotechnology). Precipitated DNA was analyzed by real time PCR using primers specific for the sterol response element (SRE)-containing region in the promoter of the SCD1 gene (SCD1-SRE) (5'-GGG AAC AGC AGA TTG CGC CTA GCC-3') (5'-GGC TAG GCG CAA TCT GCT GTT CCC-3'), random primers (5'-AGCGAACAGCAGATTGCGGCAG-3') (5'-TCTCGGCGTGCCAGAAGGGAGGT-3') in the SCD1 promoter (32), or the primer sets (5'-CCG GAC ATC AGC TGG AAC GGG-3') (5'-CCC GTT CCA GCT GAT GTC CGG-3') specific for the SRE-containing region in the promoter of the GPAT1 gene (GPAT1-SRE) or primers (5'-GGCTCACAACCATCTATAATCAGGT-3') (5'-ACAGCTTTCTGCTTGCATGTATG-3') for the control GAPDH promoter. The results are normalized to control immunoglobulin G, GAPDH, and input DNA.

    Statistical analysis. Data are presented as means ± SEM. All data were analyzed by 2-way ANOVA. Fisher's protected least squares difference test was performed when the interaction was significant. Classification factors were dietary fat, ethanol, and the interaction of both factors (dietary fat x ethanol). Differences between means were considered significant at P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Relative levels of hepatic mature SREBP-1 protein and mRNA expression of SREBP-1 regulated lipogenic enzymes. The levels of mature SREBP-1 protein were determined in the liver nuclear extract samples from the previously studied ethanol-fed and control mice (29). Compared with the HPF diet, the HSF diet tended to increase the mature SREBP-1 protein level (P = 0.09; Fig. 1A). However, the amount of mature SREBP-1 protein was greater in the livers of HPF+E diet-fed mice compared with the mice receiving only the HPF diet (P < 0.05; Fig. 1A). Conversely, the addition of ethanol to the HSF diet dramatically reduced mature SREBP-1 protein levels compared with the HSF or HPF control diet (P < 0.05; Fig. 1A). The amount of membrane-bound SREBP-1 precursor protein did not differ among the groups, suggesting that the HSF+E diet suppresses the abundance of mature processed SREBP-1.


Figure 1
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  		FIGURE 1  Representative Western blots of nuclear SREBP-1 protein (A) and relative mRNA levels of GPAT1 (B), SCD1 (C), and FAS (D) in the livers of mice fed liquid diets containing HPF or HSF with or without ethanol (E). The levels of mature SREBP-1 protein were quantified using the ratio of the ~68-kDa band to the nonspecific protein bands, indicated by an asterisk. HPF without ethanol is considered as the control and set at 1.0. Bars are means ± SEM, n = 8. The following effects were significant: GPAT1, ethanol, dietary fat x ethanol; SCD1, dietary fat x ethanol; FAS, dietary fat x ethanol. Means without a common letter differ, P < 0.05.

 
Feeding ethanol to mice fed the HPF diet increased the mRNA levels of the SREBP-1-regulated lipogenic enzymes, GPAT1, SCD1, and FAS, compared with the control diets (P < 0.05; Fig. 1). Conversely, HSF+E diet either blocked or reduced the ethanol-induced increases in mRNA levels of GPAT1, SCD1, and FAS compared with HPF+E or HPF diet (P < 0.05; Fig. 1).

    Hepatic acetylation status of histone H3-Lys9. The acetylation levels of hepatic histone H3-Lys9 of mice fed the HPF diet were similar to those of mice fed the HSF diet (Fig. 2A). However, the acetylation level of histone H3-Lys9 was enhanced by the HPF+E diet compared with the HPF control diet (P < 0.05; Fig. 2A). The ethanol-induced acetylation of histone H3-Lys9 was blocked by the HSF diet (Fig. 2A). Hepatic histone H3 protein levels did not differ among the groups (Fig. 2A). Compared with the respective control diets, feeding ethanol with either a HPF or a HSF diet did not influence overall hepatic HAT or HDAC activity in these mice (data not shown).


Figure 2
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  		FIGURE 2  Representative Western blots of acetyl-histone H3-Lys9 and histone H3 levels (A), SIRT1 and β-actin (B), acetyl-PGC-1{alpha} and PGC-1{alpha} (C), and acetyl-SREBP-1 and SREBP-1 (D) in the liver nuclear extracts of mice fed liquid diets containing HPF or HSF with or without ethanol (E). Results were quantified by a PhosphorImager. All protein levels were expressed relative to HPF control. Data are means ± SEM, n = 5–8.

 
    Relative hepatic levels of SIRT1 mRNA and protein and its activity. We tested the hypothesis that a HSF diet may prevent alcoholic fatty liver by upregulating hepatic SIRT1. Mice fed the HPF diet did not differ in their SIRT1 mRNA or protein levels from the mice fed the HSF diet. However, SIRT1 mRNA (HSF+E, 1.55 ± 0.06 vs. HSF, 1.0 ± 0.1; P < 0.05) and protein expression (P < 0.05; Fig. 2B) was increased in the livers of HSF+E mice compared with the HSF diet control. Conversely, feeding ethanol with a HPF diet modestly decreased SIRT1 mRNA (HPF+E, 0.73 ± 0.05 vs. HPF, 1.0 ± 0.1; P < 0.05) or protein expression (P < 0.05; Fig. 2B) compared with the HPF control.

To determine the effects of dietary fat on hepatic SIRT1 deacetylase activity, the acetylation status of PGC-1{alpha}, a marker of in vivo SIRT1 activity (16,19–21), was measured. The HSF+E diet decreased the ratio of acetylated PGC-1{alpha}:total PGC-1{alpha} protein compared with the control HSF diet (P < 0.05; Fig. 2C). Compared with the control HPF diet, the ratio of acetylated PGC-1{alpha}:total PGC-1{alpha} protein was substantially increased by the HPF+E diet (P < 0.05; Fig. 2C).

We analyzed acetylation levels of mature SREBP-1 protein to further determine whether acetylation of mature SREBP-1c was affected in the same fashion as PGC-1{alpha}. The ratio of acetylated mature SREBP-1:mature SREBP-1 protein was increased in the livers of the HPF+E mice compared with those of the pair-fed HPF control mice (P < 0.05; Fig. 2D).

    Association of acetylated histone H3-lys9 with GPAT1 and SCD1 promoter regions. A ChIP assay was used to assess the effects of dietary fat on the association of acetylated histone H3-Lys9 with the SCD1 and GPAT1 promoter regions in the livers of ethanol-fed mice and pair-fed control mice. The HPF+E diet increased the association of acetylated histone H3-Lys9 with both GPAT1-SRE and SCD1-SRE promoter regions compared with the control diets (P < 0.05; Fig. 3), whereas the HSF+E diet blocked the association of acetylated histone H3-Lys9 with these promoter regions (Fig. 3).


Figure 3
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  		FIGURE 3  Acetyl-histone H3-lys9 associated with the GPAT1-SRE (A) and SCD1-SRE (B) promoter regions in livers of mice fed liquid diets containing HPF or HSF with or without ethanol (E). The value for the HPF group was set at 1.0 as a control for comparison purposes. Bars are means ± SEM, n = 8. The following effects were significant: GPAT1, dietary fat x ethanol; SCD1, dietary fat x ethanol. Means without a common letter differ, P < 0.05.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
In this study, we demonstrated that a HSF diet suppressed levels of mature, nuclear hepatic SREBP-1 and subsequently prevented increases of mRNA of SREBP-1 target genes encoding the lipogenic enzymes GPAT1, SCD1, and FAS in ethanol-fed mice. Moreover, chronic ethanol administration to these HSF-fed mice significantly increased mRNA and protein levels of hepatic SIRT1 and enhanced hepatic SIRT1 deacetylase activity. The up-regulation of SIRT1 by the HSF+E diet inversely corresponded to hepatic histone H3-Lys9 acetylation levels. ChIP assays further revealed that the HSF diet reduced the association of acetylated histone H3-Lys9 with SCD1 and GPAT1 promoters in livers of ethanol-fed mice. Taken together, these findings suggest that the protective effect of a HSF diet against alcohol-induced liver steatosis may be partially mediated by stimulating hepatic SIRT1 activity, which acts to deacetylate histone H3-Lys9, which in turn results in decreased mature, nuclear SREBP-1 and decreased transcription of genes encoding lipogenic enzymes, thus preventing lipid accumulation in liver.

We previously found that a HSF diet increased the rate of hepatic fatty acid oxidation through induction of the adipocyte hormone, adiponectin, in ethanol-fed mice (29). Activation of hepatic AMPK by adiponectin is known to reduce the expression of SREBP-1c and its targeted genes encoding lipid-synthesizing enzymes (33–35). Recently, we discovered that chronic ethanol administration to micropigs on a folate-deficient diet stimulates hepatic lipid synthesis by downregulating adiponectin-mediated AMPK activity and subsequently increases the expression of mature SREBP-1c (8). Therefore, it is possible that downregulation of SREBP-1 signaling by HSF+E is partially mediated through induction of circulating adiponectin.

The precise molecular mechanism by which HSF diet plus ethanol upregulates hepatic SIRT1 remains to be determined. In liver, metabolism of ethanol by alcohol dehydrogenase and aldehyde dehydrogenase causes a shift in the redox state, resulting in marked increases in NADH and lactate and decreased NAD+ and pyruvate (22). Our current results suggest that the HSF+E diet regulates SIRT1 at multiple levels. Accumulating evidence demonstrates that SIRT1 activity is modulated by nutrient signaling largely via fluctuations in levels of NAD+ and pyruvate, NADH and lactate, or the [NAD+]:[NADH] ratio (14,16,36,37). In this scenario, increased SIRT1 activity in mice fed the HSF+E diet might be mediated by blocking the ethanol metabolism-induced shift in the ratio of [NAD+]:[NADH]. Our laboratory is currently investigating whether levels of hepatic lactate and pyruvate, which represent the relative ratio of [NAD+]:[NADH], are altered by ethanol feeding on either a HSF or a HPF diet.

Acetylation of histone H3-Lys9 is generally regarded as a specific marker of active genes (38). Ethanol exposure has been shown to increase acetylation of histone H3-Ly9 both in vitro and in vivo (38–43). In this study, we have demonstrated that a HSF diet blocked acetylation of histone H3-Lys9 and attenuated the association of acetylated histone H3-lys9 with the promoters of GPAT1 and SCD1 genes in livers of ethanol-fed mice, suggesting that the HSF diet may prevent the ethanol-mediated increase in expression of genes encoding lipogenic enzymes through blocking histone H3-Lys9 hyperacetylation.

Our previous work showed that HSF+E upregulated the hepatic PGC-1{alpha}-PPAR{alpha} axis (29). In this study, HSF blocked hepatic PGC-1{alpha} hyperacetylation in response to ethanol exposure. Whether the HSF-mediated deacetylation of PGC-1{alpha} via SIRT1 inhibition contributes to increased expression of the PPAR{alpha}-targeted enzymes involved in mitochondrial fatty acid oxidation will be of great interest to determine.

Although this study strongly suggests involvement of SIRT1 in the protective action of the HSF diet, our data are correlative in nature. The cause and effect relationship needs to be established by using hepatic SIRT1 knockout mice in the future. Moreover, it has been reported that development of alcoholic liver steatosis can also occur in the presence of suppressed SREBP-1c signaling in rats (44,45), suggesting possible involvement of complicated multiple mechanisms by which HSF protects against alcohol-induced fatty liver.

In summary, this study demonstrates for the first time to our knowledge that the protective action of saturated fat against alcohol-induced liver steatosis in mice is mediated at least in part through inactivation of hepatic SREBP-1 signaling. More importantly, our study suggests that modulation of the SIRT1-SREBP-1-histone H3 axis by a HSF+E diet may represent a novel molecular mechanism by which a HSF diet protects against development of alcoholic fatty liver.


   ACKNOWLEDGMENTS
 
We thank Ruth Ann Ross for outstanding technical contributions during the prior affiliation of the corresponding author (M. You) with the Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine.


   FOOTNOTES
 
1 Supported by NIH/NIAAA grants AA013623 and AA015951 (to M. You). Back

2 Author disclosure: M. You, Q. Cao, X, Liang, J. M. Ajmo, and G. C. Ness, no conflicts of interest. Back

5 Abbreviations used: ALLN, N-acetyl-leucinal-leucinal-norleucinal; AMPK, AMP-activated protein kinase; ChIP, chromatin immunoprecipitation; Ct, comparative threshold; FAS, fatty acid synthase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GPAT1, mitochondrial glycerol-3-phosphate acyltransferase; HAT, histone acetyltransferase; HDAC, histone deacetylase; HSF, high saturated fat; PGC-1{alpha}, PPAR{gamma} coactivator 1{alpha}; HPF, high polyunsaturated fat; SCD1, stearoyl-CoA desaturase 1; SIRT1, sirtuins 1; SRE, sterol response element; SREBP-1, sterol regulatory element-binding protein 1. Back

Manuscript received 2 October 2007. Initial review completed 4 October 2007. Revision accepted 14 December 2007.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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