Comparison of Dietary Control and Atorvastatin on High Fat Diet Induced Hepatic Steatosis and Hyperlipidemia in Rats
© Ji et al; licensee BioMed Central Ltd. 2011
Received: 13 December 2010
Accepted: 26 January 2011
Published: 26 January 2011
Treatment with atorvastatin (ATO) or dietary control has been demonstrated to benefit patients with non-alcoholic fatty liver disease (NAFLD) and hyperlipidemia. However, little is known on whether combination of dietary control and ATO treatment could enhance the therapeutic effect.
We employed a rat model of NAFLD to examine the therapeutic efficacy of dietary control and/or ATO treatment. Sprague-Dawley rats were fed with normal chow diet as normal controls or with high fat diet (HFD) for 12 weeks to establish NAFLD. The NAFLD rats were randomized and continually fed with HFD, with normal chow diet, with HFD and treated with 30 mg/kg of ATO or with normal chow diet and treated with the same dose of ATO for 8 weeks. Subsequently, the rats were sacrificed and the serum lipids, aminotranferase, hepatic lipids, and liver pathology were characterized. The relative levels of fatty acid synthesis and β-oxidation gene expression in hepatic tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Hepatic expression of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was determined by Western blot assay.
While continual feeding with HFD deteriorated NAFLD and hyperlipidemia, treatment with dietary control, ATO or ATO with dietary control effectively improved serum and liver lipid metabolism and liver function. In comparison with ATO treatment, dietary control or combined with ATO treatment significantly reduced the liver weight and attenuated the HFD-induced hyperlipidemia and liver steatosis in rats. Compared to ATO treatment or dietary control, combination of ATO and dietary control significantly reduced the levels of serum total cholesterol and low density lipoprotein cholesterol (LDL-C). However, the combination therapy did not significantly improve triglyceride and free fatty acid metabolism, hepatic steatosis, and liver function, as compared with dietary control alone.
ATO treatment effectively improved NAFLD-related hyperlipidemia and inhibited liver steatosis, accompanied by modulating the expression of genes for regulating lipid metabolism. ATO enhanced the effect of dietary control on reducing the levels of serum total cholesterol and LDL-C, but not triglyceride, free fatty acid and hepatic steatosis in HFD-induced fatty liver and hyperlipidemia in rats.
Non-alcoholic fatty liver disease (NAFLD) is a common hepatic disease, and pathologically, it can display as simple steatosis, non-alcoholic steatohepatitis (NASH), and eventually progress to cirrhosis, an end-stage liver disease. The prevalence of NAFLD ranges from 6% to 14% in different populations . The median prevalence of ultrasonographic steatosis in Chinese populations is about 10%, but varies from 1% to more than 30%. Notably, 1%-5% of patients with simple steatosis can eventually develop actual cirrhosis, and 10% to 15% of patients with NASH can progress to cirrhosis and even to hepatocellular carcinoma[4, 5].
The pathogenic process of NAFLD is not well understood and effective therapy for NAFLD has not been established. Currently, treatment for NAFLD is generally dependent on gradual loss of body weight and change in lifestyle. However, these strategies have poor compliance in many patients, and whether these strategies are still beneficial for patients with advanced disease is unknown. Numerous efforts have been directed at exploring new therapeutic reagents. Insulin receptor sensitizing agents and antioxidants have been tested for the treatment of NAFLD. However, their therapeutic efficacy and clinical safety remain to be established. Recently, several studies reveal that treatment with atorvastatin (ATO) is effective and safe for patients with NAFLD or NASH with hyperlipidemia[7, 8]. However, whether the efficacy of ATO treatment is better than dietary control and whether ATO can synergize with dietary control to enhance the therapeutic efficacy for NAFLD have not been explored.
This study aimed at examining the therapeutic efficacy of dietary control combined with ATO treatment in a rat model of NAFLD with hyperlipidemia and at exploring potential mechanism(s) underlying the therapeutic effect of dietary control and/or ATO treatment on inhibiting the high fat diet (HFD)-induced hyperlipidemia and liver steatosis.
Establishment of rat model of NAFLD
Dietary control and ATO treatment reduced the liver weight in NAFLD rats
The body weights, liver weights and the ratios of liver to body weights in rats
Liver weight (g)
Body weight (g)
12.48 ± 0.91
547.72 ± 25.95
2.28 ± 0.12
27.00 ± 3.56†
542.14 ± 34.40
4.98 ± 0.58†
13.80 ± 1.88*‡
509.11 ± 48.39
2.71 ± 0.30*‡
12.81 ± 1.16*‡
520.23 ± 28.97
2.46 ± 0.19*‡
20.92 ± 2.45*
512.11 ± 51.87
4.11 ± 0.56*
Dietary control and ATO treatment attenuated the HFD-induced hepatic steatosis
The levels of serum animotransferases and hepatic lipids in rats
Serum ALT (U/L)
Serum AST (U/L)
Hepatic TC (mg/g)
Hepatic TG (mg/g)
30.30 ± 4.79
69.60 ± 7.78
0.94 ± 0.21
1.61 ± 0.82
79.30 ± 22.23††
135.20 ± 26.52††
6.33 ± 1.59††
3.51 ± 0.77††
42.70 ± 12.72**
79.10 ± 13.4**‡
4.19 ± 1.15**‡
2.29 ± 0.95**
40.60 ± 5.50**
73.6 ± 11.26**‡
4.26 ± 1.02**‡
2.10 ± 0.79**
43.40 ± 7.41**
100.70 ± 6.04*
4.90 ± 0.27
2.53 ± 0.65*
To determine whether dietary control and ATO treatment could mitigate the HFD-induced liver injury, the concentrations of serum ALT and AST in different groups of rats were examined. The concentrations of serum ALT and AST in the model group were significantly higher than that of the normal control, DC, DCA and ATO groups. While the levels of serum ALT and AST were comparable between the DC and DCA groups. The level of serum AST, but not ALT, in the ATO group were significantly higher than that of the DC and DCA groups (Table 2).
Dietary control and ATO treatment improved serum lipid profiles
The levels of serum lipids in rats
1.45 ± 0.14
0.68 ± 0.14
0.24 ± 0.07
0.82 ± 0.14
50.14 ± 11.10
4.36 ± 1.70††
0.91 ± 0.10††
3.82 ± 1.88††
0.83 ± 0.18
63.55 ± 13.68†
2.15 ± 0.23**
0.70 ± 0.22**
1.28 ± 0.08**
0.82 ± 0.16
42.66 ± 11.89*
1.47 ± 0.19**‡
0.72 ± 0.13**
0.33 ± 0.10**‡
0.83 ± 0.16
45.33 ± 9.76*
2.35 ± 0.40*
0.75 ± 0.26**
1.30 ± 0.44**
0.82 ± 0.13
50.40 ± 13.38*
Effect of dietary control and ATO treatment on the transcription of the PPARα and SREBP-1c-related genes in the liver
Effect of dietary control and ATO treatment on the expression of HMG-CoA reductase in the liver
NAFLD is a common chronic liver disease worldwide and its incidence is increasing in developed countries . Over-consumption of high calories of foods, particularly HFD, is crucial for the development of NASH and NAFLD. Conceivably, control of diet is important for the prevention and intervention of NASH. Dietary control and lifestyle modification appear to be an effective therapeutic strategy for intervention of NAFLD in individuals with obese and insulin resistance [11, 12]. Recent studies have shown that treatment with ATO also benefits patients with NASH and NAFLD[7, 8]. In this study, we compared the efficacy of dietary control and/or ATO treatment on the HFD-induced hepatic steatosis and hyperlipidemia in rats. We found that dietary control or combined with ATO treatment for 8 weeks significantly inhibited the HFD-induced liver weights and reduced the ratios of liver to body weights in the NAFLD rats. However, we did not observe significant difference in the body weights among those groups of rats, consistent with previous reports in this model of rats[13, 14]. The reason may be that a high fat diet may induce anorexia in rats [15, 16]. Furthermore, dietary control or combined with ATO treatment mitigated the HFD-induced hepatic steatosis, which was associated with the improvement of liver and systemic lipid profiles and function, leading to reduction in the severity of hyperlipidemia in NAFLD rats. Therefore, our data support the notion that dietary control and personal lifestyle modifications are critical for the control of hyperlipidemia and associated NAFLD. However, whether dietary control for a longer period could prevent the development of NAFLD-related liver fibrosis and dietary control could improve lipid metabolism in advanced NAFLD, remain to be further investigated.
Surprisingly, treatment with ATO alone only had mild or moderate benefits for the NAFLD rats, while combination of ATO treatment with dietary control did not enhance the effect of dietary control on reducing the levels of serum and hepatic triglyceride and free fatty acid, liver injury, and hepatic steatosis in our experimental system. The present study revealed that dietary control remained a basic therapy for the NAFLD, and to some extent, this was similar to a previous report that antioxidant (alpha-tocopherol plus ascorbic acid) does not increase the efficacy of lifestyle intervention alone in NAFLD model . Apparently, treatment with ATO or antioxidant does not synergize with dietary control in inhibiting HFD-induced liver damage. Our findings were different from that the findings by Martin-Castillo et al, who found that the combination of ATO treatment with a standard diet did reduce the scores of NAFLD activity more . The difference between our and their findings may be due to different models studied.
Previous studies have shown that the transcription factors, SREBP-1c, the PPARα, and the expression of their targeting genes, such as the FAS, ACC, CPT-1, and ACO, are crucial for the development of NAFLD. The SREBP-1c can modulate the expression of a large number of genes involved in the uptake of lipoproteins, the synthesis of cholesterol, TG, and VLDL. The PPARα regulates the expression of the genes involved in mitochondrial and liver fatty acid β-oxidation. Down-regulation and deficient expression of PPARα are associated with the development of NASH, and treatment with agonist for PPARα prevents and inhibits the development of NAFLD[21, 22]. Consistently, we found that HFD increased the transcription of SREBP-1c, FAS, and ACC, but decreased the levels of hepatic PPARα mRNA transcripts in the rats while dietary control and treatment with ATO down-regulated the expression of hepatic SREBP-1c and its targeting genes, but up-regulated the transcription of PPARα mRNA in the rats. Our data were consistent with previous findings that treatment with ATO up-regulated the expression of PPARα, liver fatty acid β-oxidation, and reduced the liver TG in rats [23, 24]. Therefore, the down-regulated expression of SREBP-1c and its targeting genes that inhibiting lipogenesis, and up-regulated expression of PPARα that promoting lipid metabolism, may contribute to the therapeutic effect of dietary control and ATO treatment on the HFD-induced hyperlipidemia and liver injury in NAFLD rats.
HMG-CoA reductase contains a sterol-sensing domain and is crucial for sterol synthesis, which is negatively regulated by binding to Insig. When plasma sterol levels are low, SREBP is released by the cleavage of a membrane-bound precursor protein and migrates to the nucleus, where it binds to the sterol regulatory element (SRE) and activates the transcription of genes for HMG-CoA reductase and other enzymes involved in the cholesterol synthesis. On the other hand, elevated levels of plasma cholesterol promote the proteolytic cleavage of SREBP from the membrane ceases and protein degradation in the nuclei[25, 26]. We found that treatment with ATO at a dose that has been demonstrated to be effective and safe for the control of hyperlipidemia could significantly reduce the hepatic expression of HMG-CoA reductase. More importantly, the relative levels of hepatic HMG-CoA reductase expression in the DCA group were significantly lower than that of the ATO and DA groups of rats. The significantly reduced levels of hepatic HMG-CoA reductase may be associated with the lower levels of serum TC and LDL-C in the DCA group of rats. Our data indicate that combination of ATO treatment with dietary control may be an effective therapeutic strategy for the treatment of HFD-induced hypercholesterolemia and related cardiovascular disease.
Our data indicated that treatment with ATO had mild or moderate effect on inhibiting the progression of NAFLD and hyerlipidemia in HFD-fed rats. ATO treatment enhanced the effect of dietary control in reducing the levels of serum TC and LDL-C, but not TG, FFA, hepatic lipids and liver steatosis in HFD-fed rats.
Materials and methods
Animals and treatment
Fifty-two male Sprague-Dawley (SD) rats at 6 weeks of age and weighing 180-220 g were from the Experimental Animal Center of Guangdong Province (China), and housed in a specific pathogen free facility maintained at a cycle of 12 h light/dark and a constant temperature of 22°C~26°C, and a relative humidity of 65 ± 15%.
The rats were randomized and fed with normal chow diet (n = 14, 10% of calories derived from fat; D12450B) or high fat diet (HFD, n = 38, 60% of calories derived from fat; D12492) for 12 weeks to induce NAFLD with hyperlipidemia, as described previously [11, 12]. At the end of the 12-week induction, six rats from normal chow diet group or HFD group were randomly chosen and sacrificed. Their liver histopathology was analyzed for the development of NAFLD. Subsequently, the 32 HFD-fed rats were further randomized into four groups and continually fed with HFD (model group), with HFD and treated P.O with 30 mg/kg of ATO (Sigma-Aldrich, St. Louis, MO) (ATO group), with normal chow diet (dietary control, DC group), or with normal chow diet and treated with the same dose of ATO (combination of dietary control with ATO, DCA group) daily for 8 weeks, respectively. Rats fed with normal chow diet without exposure to HFD were used as the normal controls.
At the end of dietary control and ATO treatment, the rats were fasted for 12 hours and sacrificed. Their blood samples were collected from the abdominal aorta, and their sera were prepared by centrifugation, frozen, and stored at -20°C until analysis. Their livers were frozen in liquid nitrogen and stored at -80°C until gene expression analysis. A portion of the liver from individual rats was fixed overnight in 10% formalin for histological analysis. Two additional samples of liver tissues (150 mg) were stored at -80°C for Westernblot analysis assay and liver lipids measurement. The experimental protocols were approved by the Animal Care and Protection Committee of Sun Yat-Sen University.
Analyses of serum lipids and transaminases
The concentrations of serum total cholesterol (TC), triglyceride(TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured using the corresponding commercial enzyme kits (Biosino, Beijing, China) on an automatic biochemistry analyzer (Olympus AU600,Tokyo, Japan). The levels of serum free fatty acid (FFA) were assayed using a commercial kit, according to the manufacturer's instruction (R&D, Minneapolis, USA).
Liver triglyceride and cholesterol
Total lipids were extracted from 100 mg of liver tissues, according to the method of Bligh and Dyer . Briefly, total lipids in liver tissues were extracted with chloroform-methanol (2:1). After evaporation overnight, the extracted lipids were re-suspended in 10% triton and isopropanol, and quantified using a commercial enzyme assay kit (Biosino, Beijing, China) on an automatic biochemistry analyzer.
RNA extraction and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)
The sequences of primers
5'- GAACGGGAAGCTCACTGGC -3'
5'- GCATGTCAGATCCACAACGG -3'
Western blot analysis of HMG-CoA reductase
The expression of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
in hepatic tissue was determined by Western blot assay. Briefly, frozen liver samples were homogenized in RIPA lysis buffer containing protease and phosphatase inhibitors. After centrifuged, the protein contents in the lysates were measured using a BCA protein assay kit (Beyotime, China). Individual lysates (30 ug) were separated by 10% SDS-PAGE and electrotransferred to polyvinylidene difluoride (PVDF) membranes. After being blocked with 5% non-fat milk in Tris-buffered saline with 0.1% Tween-20 (TBST, 25 mM Tris, pH 8.0, 137 mM NaCl, 2.7 mM KCl, and 0.1% Tween-20) at room temperature for 60 min, the membranes were incubated with anti- HMG-CoA reductase or anti-GAPDH antibodies (Santa Cruze Biotechnology, Santa Cruze, USA) overnight at 4°C. The bound antibodies were detected with horseradish peroxidase (HRP)-conjugated goat anti-rabbit IgG antibodies (Santa Cruze Biotechnology) and visualized using the enhanced chemiluminescence (ECL, Pierce, Rockford, IL) system and exposed to X-ray film (Kodak, Japan).
Histological analysis of the liver
After eight weeks of intervention, the rats were sacrificed and their livers were fixed by 10% buffered formalin and embedded in paraffin. The liver sections (5 μm) were stained with hematoxylin and eosin (H&E), and the steatoic degrees of individual liver samples were examined and scored, according to the percentage of hepatocytes containing lipid droplets  by a pathologist in a blinded manner.
Values were expressed as mean ± SD. The difference among groups was analyzed by one-way ANOVA and Students t-test. The association among variants was analyzed by the least significant difference (LSD) test using the SPSS 13.0 software. The accepted level of significance was p < 0.05.
This study was supported by grants from Guangdong Natural Science Foundation (10151008901000063)
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