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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 63  |  Issue : 4  |  Page : 149-155

Administration of low-dose resveratrol attenuated hepatic inflammation and lipid accumulation in high cholesterol-fructose diet-induced rat model of nonalcoholic fatty liver disease


1 Department of Clinical Pathology, Far Eastern Memorial Hospital, New Taipei; Department of Nursing, Cardinal Tien Junior College of Healthcare and Management, Yilan, Taiwan
2 Department of Internal Medicine, Division of Cardiology, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
3 Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
4 Department and Graduate Institute of Biomedical Sciences, College of Medicine; Healthy Aging Research Center, Chang Gung University, Taoyuan City, Taiwan
5 Healthy Aging Research Center, Chang Gung University; Kidney Research Center, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
6 Kidney Research Center; Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital; College of Medicine, Chang Gung University, Taoyuan City, Taiwan
7 Department and Graduate Institute of Biomedical Sciences, College of Medicine; Healthy Aging Research Center, Chang Gung University; Kidney Research Center, Chang Gung Memorial Hospital, Taoyuan City, Taiwan

Date of Submission11-Jun-2020
Date of Acceptance20-Jul-2020
Date of Web Publication28-Aug-2020

Correspondence Address:
Prof. Li-Man Hung
Department of Biomedical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1st Road, Guishan District, Taoyuan City 33302
Taiwan
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Source of Support: This study was supported by a research grants from Chang Gung Memorial Hospital (CMRPD1K0161), CGU (EMRPD1K0381), and the Ministry of Science and Technology (MOST 105-2320-B-182-039-MY3) of Taiwan to Dr. Li-Man Hung., Conflict of Interest: None


DOI: 10.4103/CJP.CJP_43_20

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  Abstract 

Resveratrol (RSV) has been demonstrated to ameliorate nonalcoholic fatty liver disease (NAFLD) in animal studies. However, RSV was given with the dosage that ranged from 7 to 300 mg/kg body weight (BW). Hence, the study aimed to investigate the efficacy of RSV at a lower dosage on high cholesterol-fructose diet (HCFD)-induced rat model of NAFLD. In the study, male Sprague-Dawley rats were fed with HCFD for 15 weeks. RSV was also given at a daily dose of 1 mg/kg BW for 15 days or 15 weeks by oral delivery. At sacrifice, plasma and liver specimens were acquired for detections of alanine and aspartate aminotransferases, proinflammatory cytokines, and lipid contents. Histological examinations and Western blotting analysis were performed using liver tissues. The results showed that RSV administration reduced plasma levels of aminotransferases and proinflammatory cytokines including interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) in HCFD-induced NAFLD. RSV also mitigated hepatic lipid accumulation and expression of IL-1β, IL-6, and TNF-α. Besides, phosphorylation of signal transducer and activator of transcription 3 (STAT3) was reduced with RSV supplementation in the liver of HCFD-fed rats. We concluded that low-dose RSV supplementation attenuated hepatic inflammation and lipid accumulation in HCFD-induced NAFLD. The ameliorative effect of RSV on NAFLD could be associated with downregulation of phosphorylated STAT3.

Keywords: High cholesterol-fructose diet, inflammation, interleukin, nonalcoholic fatty liver disease, resveratrol, STAT3


How to cite this article:
Chang CC, Chang CY, Lin PC, Huang JP, Chen KH, Yen TH, Hung LM. Administration of low-dose resveratrol attenuated hepatic inflammation and lipid accumulation in high cholesterol-fructose diet-induced rat model of nonalcoholic fatty liver disease. Chin J Physiol 2020;63:149-55

How to cite this URL:
Chang CC, Chang CY, Lin PC, Huang JP, Chen KH, Yen TH, Hung LM. Administration of low-dose resveratrol attenuated hepatic inflammation and lipid accumulation in high cholesterol-fructose diet-induced rat model of nonalcoholic fatty liver disease. Chin J Physiol [serial online] 2020 [cited 2020 Sep 28];63:149-55. Available from: http://www.cjphysiology.org/text.asp?2020/63/4/149/293585

Chih-Chun Chang & Chieh-Yu Chang contributed equally to this work.



  Introduction Top


Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disorders worldwide. Accumulating evidence showed that a variety of medical situations, mainly including diabetes, obesity, and metabolic syndromes, were associated with NAFLD.[1],[2],[3] Nonalcoholic steatohepatitis (NASH), belonging to the severe form of NAFLD, is featured by lobular inflammation and apoptosis of hepatocytes, leading to cirrhosis and possibly hepatocellular carcinoma.[4],[5] The prevalence of NAFLD and NASH remains increasing in the past decades,[3] and it has been estimated that the prevalence of NASH ranged from 1.1% to 22.2%.[6],[7],[8],[9],[10] Hence, it is important to refrain from risk factors of NAFLD and NASH, and the development of potential pharmacologic therapies is warranted.

Resveratrol (RSV, 3,4',5-trihydroxy-trans-stilbene), a polyphenol enriched in grapes and red wine, has been demonstrated to possess numerous health benefits, including anti-oxidative and anti-inflammatory effects.[11],[12] Previous studies also revealed that RSV exerted an insulin-like effects against hyperglycemia in both streptozocin- and high-calorie diet-induced diabetic animal models.[13],[14] Recently, it was reported that RSV could suppress lipogenesis in the adipocyte cell lines.[15],[16] Besides, accumulating evidence demonstrated that RSV could retard NAFLD progression and ameliorate reduced insulin resistance via a variety of signaling pathways, such as Akt and AMP-activated protein kinase.[17],[18],[19] However, the dosage of RSV used in most of the animal studies, which ranged from 7 to 300 mg/kg body weight,[20] remained higher than that was acquired from diet or even the concentrated tablets or capsules. Whether similar regulatory events in lipid levels and anti-inflammation surround NAFLD treated with a lower dose of RSV remains to be explored.

Our previous study showed that RSV treatment at dosage of 1 mg/kg BW exerted a regulatory effect on glucose metabolisms in the muscle of high cholesterol-fructose diet (HCFD)-fed rats.[21] Here, we further established a rat model of HCFD-induced NAFLD and investigated the effects of low-dose RSV treatment on inflammation and lipid levels in the rats with NAFLD.


  Materials and Methods Top


Animals and experimental design

Sprague-Dawley male rats, aged about 6 weeks and weighed 150–170 g, were purchased from the National Laboratory Animal Breeding and Research Center (Taipei, Taiwan). All rats were housed in the animal room of Chang Gung University (CGU), with a constant temperature of 22°C ± 1°C and a fixed 12-h light/dark cycle, complying with the guidelines and manual of the committee of the care of laboratory animals of CGU. The study was approved by the Institutional Animal Care and Use Committee of CGU (Approval number CGU12-095 and CGU12-166).

The rats were randomly assigned into four groups as previously reported,[21] including control, HCFD-fed group, and HCFD-fed groups treated with RSV for 15 days and 15 weeks. In the control group, rats were fed with regular standard diet (0.275 ppm cholesterol, 5.1% fat, 23.5% protein, and 50.3% carbohydrate, LabDiet 5010). Instead, rats in HCFD-fed group were fed with high-cholesterol diet (4% cholesterol, 10.1% fat, 17% protein, and 51.6% carbohydrate, TD03468; Harlan Teklad, Indianapolis, IN, USA) with 10% fructose in drinking water for 15 weeks. For those treated with RSV, administration of RSV was given by oral gavage once per day at the dosage of 1 mg/kg BW. For sacrifice, rats were fasted overnight, anesthetized by intraperitoneal injection of pentobarbital with an overdose of 100 mg/kg, and were sacrificed for blood collection, liver weight measurement, and tissue processing.

Biochemical analysis and cytokine determination

Blood specimens were collected from the tail vein and were centrifuged for biochemical measurements after sacrifice. Plasma was separated for the measurements of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) using commercially available kits according to the manufacturer instructions (Randox reagent kits; Randox Laboratories, Antrim, UK). Plasma insulin was also determined by rat insulin enzyme-linked immunosorbent assay (ELISA) kit (Mercodia, Uppsala, Sweden). For determination of proinflammatory cytokines, including interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) in plasma and liver tissue homogenates, commercially available ELISA kits were utilized according to the manufacturer instructions (R&D Systems, Minneapolis, USA).

Detection of hepatic triglyceride and cholesterol

Approximately 250 mg liver tissues were ground by liquid nitrogen and extracted using 4 mL chloroform/methanol solution (2:1 in volume), washed, and evaporated. The nuclear magnetic resonance (NMR) spectra were obtained by dissolving the dried lipid fractions in deuterated chloroform (CDCl3; Sigma-Aldrich, St. Louis, MO, USA) containing tetramethylsilane (TMS) as an internal standard and then transferred into a 5 mm NMR tube (Wilmad Lab Glass, NJ, USA).1H NMR spectra were obtained using a 400 MHz NMR spectrophotometer (Bruker, Taiwan). The proton signals were referenced to TMS set at δ = 0.00 ppm. The chemical shifts of clearly identifiable peaks were assigned to triglyceride and cholesterol by comparing the published data on lipids. The area under the peak was calculated and normalized by tissue weight.

Liver histology by hematoxylin and eosin staining and Oil Red O staining

Liver tissues were fixed in 10% formalin and embedded in paraffin. The sections were then stained with hematoxylin and eosin (H and E) by Leica AutoStainer XL (Leica Biosystems, Nussloch, Germany), and the Permount was spread under the coverslip to cover liver tissues. The slides were examined using a Nikon Eclipse E800 microscope to observe the histological parts surrounding the central vein and portal vein. For assessment of lipid accumulation in the liver, fixed liver tissues in 10% formalin were sectioned using a frozen microtome and stained with Oil Red O.

Western immunoblotting analysis

Liver tissues were homogenized with radioimmunoprecipitation assay lysis buffer containing phosphatase inhibitor cocktail and protease inhibitor. The extracted proteins were then separated by centrifugation at 12,000 rpm for 10 min at 4°C, resolved using 8%–12% sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and transferred to the polyvinylidene difluoride membranes. After being blocked with 5% bovine serum albumin in Tris-buffered saline (TBS) at room temperature (RT) for 1 h, the blots were probed with a 1:1,000 or 1:2,000 dilution of the primary antibodies, including signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 Tyr705 (Merck Millipore, MA, USA), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Signalway Antibody Co., MD, USA) at 4°C overnight. Washed by TBS containing 1% Tween 20 (TBST), the membranes were then incubated with a 1:1,000 diluted enzyme-linked secondary antibodies at RT for 1 h. Washed by TBST again, the blots were then visualized using the chemiluminescence method (Amersham, PA, USA). Each protein band was quantified using Image J software (http://rsb.info.nih.gov), followed by densitometry reading, and undertaken either after normalization by GAPDH expression.

Statistical analysis

Data were presented with mean ± standard deviation and were analyzed by one-way analysis of variance (ANOVA), followed by post hoc test with Tukey's method for multiple comparisons using SPSS (version 19.0; SPSS Inc., Chicago, IL, USA) statistical software. The bar chart was illustrated by SigmaPlot (version 9.0; Systat Software, Inc., CA, USA). P < 0.05 was considered statistically significant.


  Results Top


Resveratrol reduced plasma levels of aminotransferases and proinflammatory cytokines in high cholesterol and fructose diet-treated rats

After dietary induction for 15 weeks, we found that both plasma ALT and AST levels were significantly increased in the HCFD-fed group when compared with control [Figure 1]. In the HCFD-fed group treated with RSV for 15 weeks, plasma AST level was significantly decreased in comparison with the HCFD-fed group. There was no obvious change of plasma ALT and AST levels after RSV treatment for 15 days. Besides, proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, were significantly increased in the plasma of the HCFD-fed group [Figure 2]. These cytokines were decreased with the treatment of RSV, especially remarkably in the group treated for 15 weeks.
Figure 1: Resveratrol reduced plasma levels of ALT (a) and AST (b) in high cholesterol and fructose diet-treated rats. *P < 0.05 versus CON. #P < 0.05 versus HCF. n = 9 in each group. CON: Age-matched control, HCF: High cholesterol-fructose diet-fed group, HCFD: High cholesterol-fructose diet-fed group treated with resveratrol for 15 days, HCFW: High cholesterol-fructose diet-fed group treated with resveratrol for 15 weeks, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase.

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Figure 2: Resveratrol reduced plasma levels of proinflammatory cytokines, including IL-1β (a), IL-6 (b), and TNF-α (c), in high cholesterol and fructose diet-treated rats. *P < 0.05 versus CON. #P < 0.05 versus HCF. n = 9 in each group. CON: Age-matched control, HCF: High cholesterol-fructose diet-fed group, HCFD: High cholesterol-fructose diet-fed group treated with resveratrol for 15 days, HCFW: High cholesterol-fructose diet-fed group treated with resveratrol for 15 weeks, IL-1β: Interleukin-1 beta, IL-6: Interleukin-6, TNF-α: Tumor necrosis factor-alpha.

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The effect of resveratrol against hepatic inflammation and lipid accumulation in high cholesterol and fructose diet-treated rats

Proinflammatory cytokines IL-1β and TNF-α in the liver were elevated in the HCFD-fed group when compared with control, and RSV treatment for 15 days and 15 weeks significantly reduced the expression of IL-1β, IL-6, and TNF-α in the liver [Figure 3]. Besides, the weight of the liver was significantly increased in HCFD-fed group [[Figure 4]a and [Figure 4]b], and adipogenesis was also observed in hepatic histology stained by H and E and Oil Red O [[Figure 4]c and [Figure 4]d]. Furthermore, there was no remarkable change of liver weight and hepatic histology in RSV-treated group. Besides, hepatic cholesterol and triglyceride levels were significantly increased in the HCFD-fed group when compared with control [Figure 5]. RSV treatment for 15 days and 15 weeks significantly decreased the concentration of hepatic cholesterol and triglyceride. These findings mentioned above suggested the anti-hyperlipidemic and anti-inflammatory effects of RSV on HCFD-induced rat model of NAFLD.
Figure 3: Resveratrol reduced proinflammatory cytokines, including IL-1β (a), IL-6 (b), and TNF-α (c), in the liver of high cholesterol and fructose diet-treated rats. *P < 0.05 versus CON. #P < 0.05 versus HCF. n = 6 in each group. CON: Age-matched control, HCF: High cholesterol-fructose diet-fed group, HCFD: High cholesterol-fructose diet-fed group treated with resveratrol for 15 days, HCFW: High cholesterol-fructose diet-fed group treated with resveratrol for 15 weeks, IL-1β: Interleukin-1 beta, IL-6: Interleukin-6, TNF-α: Tumor necrosis factor-alpha.

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Figure 4: The effect of resveratrol on liver weight (a and b) and histology stained by H and E (c) and Oil Red O (d) in high cholesterol and fructose diet-treated rats. The length of scale bar was 50 μm under ×200 magnification (c and d). *P < 0.05 versus CON. n = 4 in each group. CON: Age-matched control, HCF: High cholesterol-fructose diet-fed group, HCFD: High cholesterol-fructose diet-fed group treated with resveratrol for 15 days, HCFW: High cholesterol-fructose diet-fed group treated with resveratrol for 15 weeks, H and E: Hematoxylin and eosin.

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Figure 5: Resveratrol reduced lipid accumulation, including TG (a) and CHOL (b), in the liver of high cholesterol and fructose diet-treated rats. *P < 0.05 versus CON. #P < 0.05 versus HCF. n = 6–9 in each group. CON: Age-matched control, HCF: High cholesterol-fructose diet-fed group, HCFD: High cholesterol-fructose diet-fed group treated with resveratrol for 15 days, HCFW: High cholesterol-fructose diet-fed group treated with resveratrol for 15 weeks, TG: Triglyceride, CHOL: Cholesterol.

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Resveratrol downregulated phosphorylation of signal transducer and activator of transcription 3 in the liver of high cholesterol and fructose diet-treated rats

Western immunoblotting of liver tissues was performed, and we found that the expression of total and phosphorylated STAT3 was significantly increased in the HCFD-fed group when compared with control, and RSV treatment for 15 weeks reduced the phosphorylated STAT3 in the liver [Figure 6]. It implied that the ameliorative effect of RSV on NAFLD could be associated with modulation of STAT3 signaling pathways.
Figure 6: Resveratrol reduced phosphorylation of STAT3 in the liver of high cholesterol and fructose diet-treated rats. The western blots (a) and quantified bar charts (b) of phosphorylated STAT3 and total STAT3 which were normalized by GAPDH were shown. *P < 0.05 versus CON. #P < 0.05 versus HCF. n = 6 in each group. CON: Age-matched control, HCF: High cholesterol-fructose diet-fed group, HCFD: High cholesterol-fructose diet-fed group treated with resveratrol for 15 days, HCFW: High cholesterol-fructose diet-fed group treated with resveratrol for 15 weeks, STAT3: Signal transducer and activator of transcription 3, GAPDH: Glyceraldehyde-3-phosphate dehydrogenase.

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  Discussion Top


In this study, we demonstrated that RSV treatment, at a low dose of 1 mg/kg BW daily, alleviated hepatic inflammation and lipid accumulation in HCFD-induced NAFLD. The protective effect of RSV on HCFD-induced NAFLD could be associated with modulation of STAT3 signaling pathways.

Excessive dietary consumption of cholesterol has been demonstrated to be associated with hepatic accumulation of cholesterol, triglycerides, and oleic acid as well as decreased ratio of polyunsaturated-to-monounsaturated fatty acids,[22] leading to NAFLD. In addition, increased fructose intake could result in de novo lipogenesis and reduced β-oxidation in the liver.[23] Hence, recent studies concerning NAFLD were investigated using HCFD-fed animal models.[24],[25] Of these, hypercholesterolemia, hyperinsulinemia, and hepatic steatosis were found. Here we tried to state that hypercholesterolemia and hyperinsulinemia could be successfully induced in such a HCFD-fed model, and RSV improved hypercholesterolemia and hyperinsulinemia in our previous study. Using this model, we demonstrated the effect of RSV on HCFD-induced NAFLD, which has been barely studied.[21] In this model, administration of RSV was shown to exert an ameliorative effect on hypercholesterolemia and hyperinsulinemia. However, the efficacy of RSV on HCFD-induced NAFLD was limitedly surveyed.

A large amount of RSV-treated NAFLD rat models with various treatment dosages and periods have been reported, most of which indicated that RSV administration reduced liver weight and hepatic lipid accumulation as well as improved fatty liver in histology.[20],[26],[27],[28],[29] Besides, it has been demonstrated that RSV attenuated insulin resistance and oxidative stress in the rat model of diet-induced NAFLD.[28],[29] Notably, Bagul et al. reported that administration of RSV at a dose of 10 mg/kg BW daily for 8 weeks exerted the protective effects against NAFLD.[28] Compared to our previous study, either administrations of RSV at a lower dose of 1 mg/kg BW for 15 days or 15 weeks ameliorated hypercholesterolemia and hyperinsulinemia in HCFD-induced NAFLD.[21] In the present study, though liver weight and fatty liver histology were not apparently decreased, the content of triglyceride and cholesterol was significantly reduced after RSV treatment at a dose of 1 mg/kg BW for both 15 days and 15 weeks. Such low dose of RSV administration for 15 weeks also reduced plasma and hepatic cytokine expressions and downregulated phosphorylation of STAT3, suggesting the anti-hyperlipidemic and anti-inflammatory effects of RSV at a low dose on HCFD-induced rat model of NAFLD.

Nowadays, the tablet and capsule of concentrated RSV have been commercially available. People are able to acquire RSV supplement by not only dietary intake but also ingestion of nutritional supplements. Several investigations of RSV supplement on human health and NAFLD have been performed in clinical trials. However, there was insufficient evidence to support the beneficial effects of RSV on NAFLD in randomized clinical trials with daily dose of 300–3000 mg, maintaining 2–6 months.[30],[31],[32],[33] It was revealed that RSV supplementation did not decrease serum aminotransferases and proinflammatory cytokines and did not ameliorate hyperlipidemia and hyperinsulinemia among patients with NAFLD in the pooled results of meta-analyses.[34],[35] Of these trials, Chen et al. showed that RSV supplementation significantly reduced TNF-α and IL-6 levels at a daily dose of 300 mg for 3 months in patients with NAFLD.[30] Besides, Faghihzadeh et al. demonstrated that RSV administration improved ALT level and hepatic steatosis in NAFLD at a daily dose of 500 mg for 12 weeks.[33] Notably, the dosage of RSV given was relatively low in these two trials when compared with another two. Although we disclosed the different dosage effect of RSV on 3T3-L1 cells,[16] and it was reported that the peak plasma concentration and half-life of RSV were 15.2 ± 5.18 μg/mL and 0.3 ± 0.2 h in Wistar rats administrated orally at a single dosage of 15 mg/kg BW,[36] and were 71.18 ng/mL and 5.1 h after oral administration of a single dose of 500 mg free RSV in healthy volunteers,[37] whether RSV supplementation with a lower dose exerted a beneficial efficacy on patients with NAFLD remains unknown and further clinical trials are warranted.

To summarize, our present study revealed that administration of RSV at a low dose of 1 mg/kg BW per day reduced hepatic inflammation and lipid accumulation in HCFD-fed rat model of NAFLD. The ameliorative effect of RSV on HCFD-induced NAFLD could be associated with downregulation of STAT3 phosphorylation.

Acknowledgments

This study was supported by a research grants from Chang Gung Memorial Hospital (CMRPD1K0161), CGU (EMRPD1K0381), and the Ministry of Science and Technology (MOST 105-2320-B-182-039-MY3) of Taiwan to Dr. Li-Man Hung.

Financial support and sponsorship

This study was supported by a research grants from Chang Gung Memorial Hospital (CMRPD1K0161), CGU (EMRPD1K0381), and the Ministry of Science and Technology (MOST 105-2320-B-182-039-MY3) of Taiwan to Dr. Li-Man Hung.

Conflicts of interest

There are no conflicts of interest.



 
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