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Research on the effects of L-carnitine and trans-chalcone on endoplasmic
reticulum stress and oxidative stress in high-fructose corn syrup-fed rats
Article in Nutrition & Food Science · June 2020
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Research on the e
ffects of
L-carnitine and trans-chalcone on
endoplasmic reticulum stress and
oxidative stress in high-fructose
corn syrup-fed rats
Velid Unsal
Department of Nutrition and Dietetics, Faculty of Health Sciences, Mardin Artuklu University, Mardin, Turkey
Köksal Deveci
and
Zeliha Cansel Ozmen
Department of Biochemistry, Faculty of Medicine, Gaziosmanpasa University,
Tokat, Turkey, and
Mehmet Kemal Tumer
Department of Oral and Maxillofacial Surgery, Faculty of Dentistry,
Gaziosmanpasa University, Tokat, Turkey and Department of Medical Biology,
Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey
Abstract
Purpose–The debate on the metabolic effects of high fructose corn syrup (HFCS) continues. The deterioration of endoplasmic reticulum (ER) homeostasis is called ER stress. Glucose-regulated protein-78 (GRP-78) and X-box binding protein-1 (XBP-1) are key markers of ER stress and the therapeutic targets of diseases. Sterol regulatory element binding protein-1c (SREBP-1c) is the most important transcription factor that regulates the expression of enzymes for fatty acid synthesis. The purpose of this paper is to research the effects of L-carnitine and trans-chalcone on ER stress and oxidative stress parameters, and to explore the therapeutic potential of L-carnitine and trans-chalcone molecules.
Design/methodology/approach–Forty male wistar albino rats randomly selected were divided into five groups. All groups are fed with standard chow (ad libitum). While Group I was fed with drinking water, Group II, III, IV and V were fed with water containing 15% HFCS. L-carnitine was given to Group IV and trans-chalcone to Group V, and both were dissolved with DMSO and given intraperitoneally. Group III was not given anything additional.
Findings–While the amount of water consumption of HFCS-fed rats has increased, the amount of feed consumption has decreased. The weights of rats in Group II and Group III have increased significantly compared to Group I (p = 0.001, p = 0.001 respectively). In Group III, GRP78, XBP-1; malondialdehyde level (p< 0.001, p = 0.001, p = 0.041); total cholesterol, triglyceride, LDL levels (p = 0.001, p < 0.001, p = 0.009, p = 0.001, respectively) have increased significantly.
Originality/value–To the best of the authors’ knowledge, this study is the first report to show that excessive HFCS consumption causes oxidative stress and ER stress. The antioxidant and antiobesity
This study was supported by a grant from Gaziosmanpasa University, Tokat, Scientific Research Projects Commission Presidency (Project No: 2016/90).
Conflicts of interest: The authors declare that there is no conflict of interest.
E
ffects of
L-carnitine and
trans-chalcone
345
Received 6 May 2020 Revised 27 May 2020 Accepted 27 May 2020Nutrition & Food Science Vol. 51 No. 2, 2021
pp. 345-361
© Emerald Publishing Limited 0034-6659 DOI10.1108/NFS-05-2020-0162
The current issue and full text archive of this journal is available on Emerald Insight at: https://www.emerald.com/insight/0034-6659.htm
properties of trans chalcone have been demonstrated. Extensive experimental and clinical studies should be conducted.
Keywords Rat, Oxidative stress, Endoplasmic reticulum stress, High-fructose corn syrup, L-carnitine, Trans-chalcone
Paper type Research paper
1. Introduction
In recent years, serious scientific discussions about the endocrine and potential health
effects of high fructose corn syrup (HFCS) have been going on vehemently. The consumption of HFCS present in drinks has been shown to cause an increase in weight gain
and obesity (Bray et al., 2004). HFCS is one of the most widely used sweeteners in the food
industry (Johnson et al., 2007). Numerous animal studies have been conducted on the effects
of diets enriched with fructose or sucrose. In these studies, it is stated that high fructose/high sucrose diets lead to various metabolic and cardiovascular effects such as dyslipidemia,
insulin resistance, hypertension, hyperuricemia, cancer and weight gain (Johnson et al., 2009;
Fouret et al., 2018;Tappy and Lê, 2010;Goncalves et al., 2019). L-carnitine is an antioxidant
and prevents the accumulation offinal products of lipid oxidation (Karlic and Lohninger,
2004; Schlaepfer and Joshi, 2020). L-carnitine protects enzymes such as superoxide
dismutase (SOD), glutathion peroxidase (GSH-Px), catalase (CAT) which are important
enzymes of the antioxidant system, against peroxidative damage (Binienda and Ali, 2001).
Trans-chalcone structure pioneers the flavonoids and chalcone compounds and has a
number of therapeutic properties, such as antioxidant, cytotoxic, anticancer, antimicrobial,
antiprotozoal, antiulcer, antihistamine and anti-inflammatory (Bitencourt et al., 2013;
Mahapatra and Bharti, 2016;Karimi-Sales et al., 2019). In addition, trans-chalcone is an
inhibitor of fatty acid synthase anda-amylase (Najafian et al., 2011).
As many enzymes involved in lipid metabolism are found in ER, ER is the main region of
lipid metabolism. Cell response in the event of homeostasis in ER; ER is defined as stress. To
cope with this stress, cells play an important role in maintaining unfolded protein response (UPR) metabolic and lipid homeostasis by activating a signal delivery system that binds the
cytoplasm called the UPR and the nucleus (Kammoun et al., 2009;Han and Kaufman, 2016)
GRP-78 leads to activation of the ER stress transducers and the initiation of the subsequent
signal cascades. Therefore, GRP-78 is seen as an“ER stress biomarker stress” because it is
the key regulator in the initiation of ER stress (Bukau et al., 2006).
Fatty acid synthase (FAS) is the regulatory enzyme for hepatic lipid synthesis. Insulin regulates the transcription and activation of the liver sterol regulatory element binding protein-1c (SREBP-1c), which participates in liver fatty acid synthesis by stimulating FAS expression. Hyperactivation of SREBP-1c induces hepatic lipid accumulation, suggesting
that SREBP-1c-associated de novo lipogenesis is the mobile target of hepatic steatosis (Li
et al., 2014;Li et al., 2016). Saturated fatty acids such as palmitate and stearate are inducers
of ER stress in various cell types (Guo et al., 2007). Studies with FAS inhibitors have been
found in recent studies. For example, mice treated with FAS inhibitors show decreased
appetite and significant weight loss. Therefore, FAS is considered as a therapeutic target,
which represents an important link in nutritional regulation (Liang et al., 2013). In the
literature, molecules such as Orlistat, Cerulenin, resveratrol, Epikatechin gallate, Luteolin,
Quercetin, Amentoflavone, Curcumin, Cocoa, Diosgenin are defined as FAS inhibitors
(Pandey et al., 2012;Zhang et al., 2016). An equilibrium shift in favor of oxidants between
oxidants and antioxidants is called oxidative stress. There are numerous studies showing the general effect of oxidative stress on signaling pathways. The most important of the
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signal molecules are reactive oxygen species (ROS). SOD, CAT, GSH-Px activities are
antioxidant enzymes that eliminate these oxidants and reduce oxidative stress (Unsal, 2018;
Higa and Chevet, 2012).
The aim of this study was tofind the effects of HFCS on weight and lipid profile, to
research the effects of L-carnitine and trans-chalcone on ER stress and oxidative stress parameters, and also to explore the therapeutic potentials of L-carnitine and trans-chalcone molecules.
2. Materials and methods 2.1 Animal groups
Our study is conducted under the control of veterinary surgeon in Gaziosmanpasa University
Medical Sciences Experimental Research and Application Center by the ethics committee
approval of Gaziosmanpasa University (2016 HADYEK-39) in accordance with the Universal
Declaration of Animal Rights of Strasbourg 1986. All animals are kept under observation for several days before the study to see whether they are healthy. For this study, 40 healthy adult
male wistar albino rats of 6–11 -week age weighing 200–350 g are used. Before starting the
study, rats are randomly divided intofive groups according to the procedure. The rats are
housed in plastic cages with eight animals per cage. HFCS (55% of fructose, 45% of glucose) is mixed with drinking water and given to rats in 750-ml plastic bottles without any restriction. HFCS-containing waters are prepared as 15%. Rats capable of performing their normal
activities in cages are kept in rooms set at 226 2°C, humidity (50–70%) and 12 h day/night.
Feed consumption amounts of groups are checked from thefirst week. On Mondays, the cages
are filled with a fixed chow (1500 g) sufficient for a week. On the following Monday, the
remaining chow is weighed and the chow consumed for one week by each cage is calculated. Compositions of standard chow: Energy (kcal/g): 3,5; % 75 Carbohydrate; % 10 Fat; % 15 protein
Group I: Nothing has been given additionally for 12 weeks. They are fed with drinking water and standard chow.
Group II: They are fed for 12 weeks with standard chowþ 15% HFCS-containing waters
(55% of fructose, 45% of glucose) solution. They are given 250ml as DMSO/3 days i.p.
Group III: They are fed for 12 weeks with standard chowþ 15% HFCS-containing waters
(55% of fructose, 45% of glucose) solution.
Group IV: They are fed for 12 weeks with standard chowþ 15% HFCS-containing
waters (55% of fructose, 45% of glucose) solution. They are given L-carnitine dissolved in DMSO as 100 mg/kg/3 days i.p.
Group V: They are fed for 12 weeks with standard chowþ 15% HFCS-containing waters
(55% of fructose, 45% of glucose) solution. They are given trans-chalcone dissolved in DMSO as 20 mg/kg/3 days i.p.
At the end of 12th week, the study is terminated. The rats are sacrificed by drawing their
blood under ketamine-xylazine anesthesia. The taken blood samples are centrifuged at
3208 g for 5 min and serum is obtained. Besides, liver tissues of the rats are taken. The
samples are delivered to the biochemistry laboratory as soon as possible for biochemical
analysis and kept at80°C until the working time. Obtained from homogenization of liver
tissue, SOD, GSH-Px, CAT enzyme activity and GSH of supernatants and homogenates, and the levels of malondialdehyde (MDA), PC, NO of homogenates are studied.
2.2 Biochemical analysis
2.2.1 Determination of superoxide dismutase activity. Determination of SOD activity is based on the method of Sun et al., the reduction of nitrous oxide (NBT) of superoxide
E
ffects of
L-carnitine and
trans-chalcone
produced by xanthine/xanthine oxidase system. The enzyme activity is determined by
measuring the absorbance of the colored formazone at 560 nm (Sun et al., 1988).
2.2.2 Determination of glutathion peroxidase activity. According to the method ofPaglia
and Valentine (1967), GSH-Px catalyzes the oxidation of reduced glutathione to oxidized
glutathione in the presence of hydrogen peroxide. The enzyme activity is calculated by measuring the absorbance decrease at 340 nm during the oxidation of NADPH used in this reaction to NADP.
2.2.3 Determination of catalase activity. CAT activity is measured according to Aebi
method. The basis of the method is based on the determination of H2O2decomposition rate
at 240 nm and the constant velocity at k (s 1, k) (Aebi, 1974).
2.2.4 Determination of malondialdehyde level. MDA and other thiobarbituric
acid-reactive substance (TBARS) reacting with thiobarbituric acid at 90–95°C, form a pink color
chromogen. After 15 min, the absorbances of rapidly cooled samples are read spectrophotometrically at 532 nm to measure MDA levels. The results are determined according to the standard graph prepared from measurements made with standard solution
(1,1,3,3-tetramethoxypropane) (Esterbauer and Cheeseman, 1990).
2.2.5 Determination of NO level. It is determined by spectrophotometric measurement of the color at 545 nm resulting from Griess reaction and nitrite sulfanilamide produced by
modified cadmium reaction and the corresponding N-naphthylethylenediamine (NNDA)
diazotization reaction (Cortas and Wakid, 1990).
2.2.6 Determination of protein carbonyl content. By reacting with the carbonyl content of the 2,4-dinitrophenylhydrazine solution prepared in hydrogen chloride, the precipitation which is washed three times with ethanol/ethyl acetate mixture is measured spectrophotometrically at 360 nm after being dissolved in 100 mM NaOH solution in the next step (Levine et al., 1990).
2.2.7 Determination of glutathione level. It is made according to the method described by Ellman. The measurement procedure of the method is that the glutathione present in the analysis tube reacts with 5,5-dithiobis 2-nitrobenzoic acid to give a yellow-greenish color and the intensity of this color is measured at a wavelength of 410 nm by spectrophotometer
to determine the amount of reduced GSH (Ellman, 1959).
2.2.8 Determination of protein. The amount of protein in the tissues is determined by the
method of protein measurement ofLowry et al. (1951).
2.2.9 Elisa. Before the homogenization process of tissue samples separated for ELISA,
0.5 g of 10 volumes (weight/volume 1: 10) of 0.01 N pH = 7.2–7.4 phosphate buffer is added to
the tissues. Tissues are homogenized for 3 min at 16,000 rpm. Then homogenates are
centrifuged at 3208g þ4°C for 15 min and the supernatants are taken. From these
supernatants, GRP-78, XBP-1 levels of ER stress markers and lipid synthesis markers FAS activity and SREBP-1c level are determined by ELISA method.
2.2.9.1 Determination of GRP-78, XBP-1, SREB-1c levels and FAS activity. GRP-78, XBP-1, FAS, SREB-1c levels from both liver tissue and serum of rats are determined
according to the manufacturer’s test procedure on Organon Teknika Microwell System by
the method of sandwich Enzyme-Linked Immunosorbent Assay (ELISA) using ELISA kit. The Elisa kits are supplied from Elabscience Biotechnology Co., Ltd (USA). CV% of the kits is below 10.
2.2.9.2 Determination of total cholesterol, LDL, HDL, TG, VLDL levels. The total
cholesterol, LDL, HDL, TG levels in the serum of the rats are studied on the“Beckman
Coulter Unicell DxC 800 Syncron Clinical System” in Gaziosmanpasa University Health
Research and Application Hospital Biochemistry Laboratory. Serum VLDL cholesterol
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levels were calculated using the Friedewald et al. (1972) formula. (VLDL cholesterol: Triglyceride/5)
2.3 Data analyses
Statistical analysis of the results is made by using ‘SPSS 21.0 for Windows package
program. When parametric test assumptions are provided, descriptive statistics; are shown
as mean6 standard deviation for the variables with normal distribution. The significance
of the differences among groups in terms of mean is researched by ANOVA test. In the
ANOVA test, Tukey method from“post-hoc” is used to find out which group reveals the
difference among groups. Paired t test is used as a comparison method for researching the difference among intra-group times at the beginning and at the end of the experiment. Pearson Correlation analysis is performed to determine the relationship between the
parameters. Results for p< 0.05 are considered statistically significant.
3. Results
3.1 Experimental animals
The weekly water consumption amounts of the animals fed with HFCS-containing water are
observed to have increased significantly. The mean chow consumption amount of Group I is
compared to the chow consumption amounts of other groups, it is statistically significant
(p< 0.001). From the beginning of the study to the end of the study, % weight changes of
Group II, Groups III and Group IV are significant (p = 0.001, p = 0.001, p = 0.022,
respectively) Abdominal fat was high in Group II and Group III (Table 1).
3.2 Biochemical analysis
3.2.1 Determination of serum TG, total cholesterol, HDL, LDL, VLDL levels. TG, Total
Cholesterol, LDL, VLDL levels of groups fed with HFCS have increased significantly
compared to Group I fed with drinking water (p< 0.001, p = 0.001, p = 0.009, p = 0.001,
respectively). Group III has the highest TG, Total Cholesterol, LDL, VLDL levels (Table 2).
3.2.2 Grp-78, XBP-1, SREBP-1c levels and FAS activities in liver tissue of groups.
GRP-78, XBP-1, SREBP-1c levels and FAS activity are statistically significant when compared
between-groups (p< 0.001, p < 0.001, p = 0.019, p < 0.001, respectively) (Table 3). There is a moderate positive correlation between weight and GRP78, XBP1, SREBP-1c groups and it is important (r = 0.46, p = 0.003; r = 0.43, p = 0.005; r = 0.42, p = 0.006; respectively). There is a moderate positive correlation between LDL levels and GRP-78 levels of groups, and it is
significant (r = 0.46, p = 0.003).
When GSH-Px activities in liver tissue of groups are examined; GSH-Px activities of groups fed with HFCS have decreased compared to Group I. The decrease in Group III is
significant (p < 0.001). When MDA levels in liver tissue of groups are examined; MDA level
of Group III has increased significantly compared to Group I (p = 0.041). MDA levels of
Group IV and Group V have decreased significantly compared to Group III (p = 0.004 and
p< 0.001, respectively). When NO levels in liver tissue of groups are examined; NO level of
Group III has increased significantly compared to Group I (p = 0.002) (Table 4). In
intra-group comparisons, GSH level of Group III with HFCS has decreased significantly in tissue
compared to Group I (p = 0.007).
Correlation analysis between tissue SOD, CAT, GSH-Px Activities, MDA, PC, GRP-78, XBP-1, SREBP-1c Levels, FAS Activities and Weight
There are weakly negative correlation between SOD activity GRP-78, FAS and
SREBP-1c levels of groups, and it is significant (r = 0.37, p = 0.048; r = 0.37 p = 0.048; r = 0.39 p =
0.012; r =0.35 p = 0.024; respectively).There are mean-positive correlation between MDA
E
ffects of
L-carnitine and
trans-chalcone
12 weeks Group I Group II Group III Group IV Group V Original body weight (g) 307.1 6 38.4 269.8 6 32.4 254 6 25.7 308.2 6 33.1 302 6 36.7 Body weight at the 12th week (g) 324.7 6 37.6 343.2 6 8.8 415 6 26.15 abde 358.5 6 28.2 326 6 31.2 % weight change (þ ) 5.7 26.3 63.3 16.3 7.9 Chow consumption (g) 1395 6 53.0 bcde 855.7 6 100.2 810.7 6 173.6 913.0 6 69.4 919 6 114.4 Energy in chow (kcal/g) 4882.5 6 185.5 2994.9 6 350.7 2838.4 6 607.6 3196.5 6 242.9 3216.5 6 400.4 Water consumption (ml) 2518.6 6 115.6 bcde 3618,0 6 144.8 3905.6 6 74.5 3477.3 6 218.7 3463 6 127.3 Abdominal fat (g) 10.11 6 4.6 15.33 6 5.3 ac 20.45 6 6.5 abde 13.56 6 4.9 bc 12.74 6 3.9 bc Liver Wt(g) 9.24 bcde 10.78 acde 11.92 abde 10.01 abc 10.07 abc Notes: aDifferent from Group I, bDifferent from Group II, cDifferent from Group III, dDifferent from Group IV, eDifferent from Group V. Data are expressed as mean 6 standard deviation (n = 8). Values in the same rows with different letters (a – e) are statistically different (p < 0.05). The signi fi cance of the differences among groups in terms of mean is researched by ANOVA test. In the ANOVA test, Tukey method from “post-hoc ” is used to fi nd out which group reveals the difference among groups Table 1. The food intake, body weight and parameters associated with obesity in each group
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level and GRP-78, XBP-1, SREBP-1c levels of groups, and it is significant (r = 0.44 p = 0.001; r = 0.58 p = 0.001; r = 0.5 p = 0.001; respectively) (Table 5).
Serum SOD, GSH-Px Activities and MDA, PC, NO, GSH Levels
MDA, PC, NO levels of Group III are high compared to other groups. SOD, GSH-Px activities of Group IV and Group V approached Group I fed with drinking water. Although
not significant, it is consistent with liver tissue data. In intra-group comparisons, GSH level
of Group III with HFCS has decreased significantly in serum compared to Group I (p = 0.04)
(Table 6).
4. Discussion
This study provides information on the metabolic effects of nutrition with HFCS, such as
weight change and lipid profile, as well as providing evidence on how nutrition with HFCS
affects oxidative stress and endoplasmic stress at the cellular level. Thefirst evidence in our
study is that the weight of the rats of the groups drinking HFCS significantly increased
compared to the group consuming the drinking water.Jürgens et al. (2005)investigated the
effects of three different drinks prepared with 15% of fructose, 10% of sucrose and synthetic
Table 2. Serum TG, total cholesterol, HDL, LDL, VLDL levels
Group Total cholesterol (mg/dl) LDL (mg/dl) HDL (mg/dl) VLDL (mg/dl) TG (mg/dl) Intergroup comparison r< 0.001 r 0.01 r 0.6 r< 0.001 r< 0.001 Group I 32.66 9.3bc 8.6 6 2.7c 41.9 6 6.9 7.66 4.3c 37.6 6 22.0c Group II 45.36 9.02a 9.56 2.08 39.26 8.9 10.66 3.2 52.66 12.1
Group III 62.26 5.5ad 12.56 1.6a 41.36 4.40 17.36 2.9ade 86.66 15.5ade Group IV 47.26 5.7c 10.56 1.85 39.86 4.33 9.26 2.4ce 46.66 15.0ce
Group V 37.76 22.0c 9.4
6 2.6 37.66 5.2 12.126 3.7c 61.0
6 18.6c
Notes:aDifferent from Group I, bDifferent from Group II,cDifferent from Group III, dDifferent from
Group IV,eDifferent from Group V. Data are expressed as mean6 standard deviation (n = 8). Values in the same rows with different letters (a–e) are statistically different (p < 0.05). The significance of the differences among groups in terms of mean is researched by ANOVA test. In the ANOVA test, Tukey method from “post-hoc” is used to find out which group reveals the difference among groups. LDL: Low-density lipoprotein, HDL: High-density lipoprotein, VLDL: Very-low-density lipoprotein, TG: Triglyceride
Table 3. Liver tissue GRP-78, XBP-1, SREBP-1c levels and FAS activities
Group GRP-78 ng/ml XBP-1 ng/ml FAS ng/ml SREBP-1c ng/ml Intergroup comparison r< 0 .001 r< 0.01 r 0.019 r< 0 .001 Group I 37.06 2.1c 2.26 0.09ce 17.46 1.09c 1.86 0.2c Group II 40.96 4.4 2.46 0.1de 19.1
6 1.7 2.16 0.5 Group III 44.66 2.9ade 2.546 0.08ade 20.06 1.2a 2.46 0.3ade Group IV 36.66 3.15c 2.2
6 0.1bc 19.09
6 1.4 1.716 0.1c
Group V 37.86 2.8c 2.26 0.1abc 18.96 1.62 1.66 0.21c Notes:aDifferent from Group I, bDifferent from Group II,cDifferent from Group III, dDifferent from
Group IV,eDifferent from Group V. Data are expressed as mean
6 standard deviation (n = 8). Values in the same rows with different letters (a–e) are statistically different (p < 0.05). The significance of the differences among groups in terms of mean is researched by ANOVA test. In the ANOVA test, Tukey method from “post-hoc” is used to find out which group reveals the difference among groups. GRP-78: Glucose-regulated protein 78, XBP-1: X-box binding protein 1, FAS: Fatty acid synthase, SREB-1c: Sterol regulatory element-binding protein 1
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ffects of
L-carnitine and
trans-chalcone
Group SOD U/mg protein CAT k/g protein GSH-Px U/g protein MDA nmol/g wet tissue PC nmol/mg protein NO m mol/g wet tissue GSH nmol/mg protein Inter-group r 0.03 r 0.6 r< 0.001 r< 0.001 r 0.2 r 0.003 r 0.01 Group I 0.03 6 0.005 1.9 6 0.9 4.6 6 1.2 bc 11.4 6 4.2 c 0.2 6 0.05 3.5 6 0.1 ce 1.0 6 0.2 c Group II 0.02 6 0.003 1.3 6 0.95 2.1 6 1.0 a 13.5 6 2.75 e 0.2 6 0.07 3.6 6 0.1 0.9 6 0.1 Group III 0.02 6 0.005 1.4 6 0.98 2.8 6 0.89 a 16.1 6 3.69 ade 0.3 6 0.07 3.8 6 0.08 a 0.7 6 0.1 a Group IV 0.02 6 0.004 1.8 6 0.8 3.5 6 0.8 10.0 6 0.2 c 0.20 6 0.08 3.6 6 0.2 0.9 6 0.3 Group V 0.026 6 0.002 1.43 6 0.3 3.35 6 1.1 8.31 6 0.3 bc 0.240 6 0.08 3.8 6 0.09 a 0.8 6 0.2 Notes: aDifferent from Group I, bDifferent from Group II, cDifferent from Group III, dDifferent from Group IV, EDifferent from Group V. Data are expressed as mean 6 standard deviation (n = 8). Values in the same rows with different letters (a – e) are statistically different (p < 0.05). The signi fi cance of the differences among groups in terms of mean is researched by ANOVA test. In the ANOVA test, Tukey method from “post-hoc ” is used to fi nd out which group reveals the difference among groups. SOD: Superoxide dismutase, CAT: Catalase, GSH-Px: Glutathione peroxidase, MDA: Malondialdehyde, PC: Protein carbonyl, NO: Nitric oxide, GSH: Glutathione Table 4. Oxidative stress parameters in liver tissue
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352
sweetener on body weight in mice for 73 days. They reported that body weight of fructose
group mice has increased significantly compared to the other groups. In their study,Light
et al. (2009)gave rats 13% of glucose, sucrose, fructose and HFCS for eight weeks. At the end
of the study, body weight of rats with sucrose has not increased significantly compared to
body weight of the control group rats, whereas body weight of HFCS group rats is reported
to have a significant increase.Oliveira et al. (2020)reported a significant increase in body
weight, TG and VLDL levels of rats fed on a high-sugar diet for 18 weeks.Bocarsly et al.
(2010)examined the short- (8 weeks) and long-term (6–7 months) effects of HFCS on body
weight and TG levels in rats treated with HFCS in different concentrations lasted seven months. At the end of the study, they observed weight gain and excessive increase of
TG. Thefindings of these studies are similar to our findings. Therefore, it can be concluded
that excessive HFCS consumption can cause obesity and HFCS increases TG and VLDL levels.
Lee et al. (2016)reported that L-carnitine supplementation has reduced significantly
adipose tissue accumulation and body weight in rats fed with high-fat diet. However, in our
study, the average weight change of the rats in the group given L-carnitine wasþ 16.30%.
Still, L-carnitine prevented weight gain. In our study, although the rats given trans-chalcone were fed with HFCS, their body weight gain was not high. These data brought us to the mind that the chalcone molecule is anti-weight. In addition, we interpreted that
trans-chalcone is a better anti-weight than L-carnitine.Jürgens et al. (2005)reported that there has
been a decrease in chow consumption of rats fed with water containing 10% of sucrose and
15% of fructose.Jürgens et al. (2005)interpreted that mice supply the required energy from
the high carbohydrate in drinking water; thus, there is a decrease in the chow consumption.
In our study, water consumption of groups fed with HFCS has increased significantly
compared to the control group. However, chow consumption of groups fed with HFCS has decreased compared to the control group. In the light of these results, we believe that the decrease in chow consumption of groups fed with HFCS is due to increased HFCS
consumption and the rats supply the energy requirement from HFCS.Zhang et al. (2012)
gave female CD-1 mice 30% of fructose solution for eight weeks and observed almost half-decrease in chow consumption amount of groups fed with HFCS. In their study, they found a
significant increase in LDL, total cholesterol levels in serums of rats fed with HFCS. In their
study,Jalalvand et al. (2015)gave trans-chalcone for eight weeks to mice fed with high-fat
diet and at the end of the study, they found that TG, total cholesterol levels have decreased
and HDL level has increased in the group with trans-chalcone. Rajasekar et al. (2007)
Table 5. Correlation analysis between weight and tissue SOD, CAT, GSH-Px, FAS activities, tissue MDA, PC, GRP-78, XBP-1, SREBP-1c levels
SOD CAT GSH-Px MDA PC
r p r p r p R p r p GRP-78 0.38 0.048 0.05 0.75 0.25 0.118 0.44 0.001 0.34 0.03 XBP-1 0.41 0.008 0.08 0.62 0.27 0.092 0.58 0.001 0.23 0.14 FAS 0.39 0.012 0.04 0.8 0.22 0.161 0.26 0.103 0.08 0.61 SREBP-1c 0.36 0.024 0.017 0.9 0.23 0.150 0.5 0.001 0.28 0.07 Weight 0.11 0.501 0.132 0.418 0.19 0.22 0.3 0.05 0.23 0.16 Notes: Pearson correlation analysis was performed to determine the relationship between parameters. P< 0.05 results were considered statistically significant. Correlation coefficient was shown with “r”. SOD: Superoxide dismutase, CAT: Catalase, GSH-Px: Glutathione peroxidase, MDA: Malondialdehyde, PC: Protein carbonyl, NO: Nitric oxide, GSH: Glutathione, GRP-78: Glucose-regulated protein 78, XBP-1: X-box binding protein 1, FAS: Fatty acid synthase, SREB-1c: Sterol regulatory element-binding protein 1
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Group SOD (U/ml) GSH-Px (U/l) MDA ( m mol/L) P (nmol/ml) NO ( m mol/L) GSH nmol/ml Intergroup comparison P 0.8 P 0.1 p 0.15 P 0.11 p 0.7 p 0.01 Group I 11.0 6 1.0 1015.2 6 312.4 c 0.2 6 0.05 bc 361.6 6 69.1 c 194.8 6 10.1 172.9 6 19.1c Group II 10.95 6 2.24 1012.2 6 307.2 c 0.31 6 0.11 392.7 6 112.1 c 193.0 6 6.5 158.2 6 8.1 Group III 10.4 6 1.6 710.9 6 301.9 ade 0.36 6 0.10 ade 470.4 6 152.1 abde 196.1 6 9.5 158.6 6 4.1 Group IV 10.2 6 2.01 1027.2 6 145.7 c 0.27 6 0.13c 342.6 6 63.8 c 193.5 6 4.8 152.2 6 6.5a Group V 11.3 6 2.0 905.4 6 185.0 c 0.25 6 0.06 c 365.5 6 72.0 c 191.0 6 5.3 164.0 6 8.8 Notes: aDifferent from Group I, bDifferent from Group II, cDifferent from Group III, dDifferent from Group IV, eDifferent from Group V. Data are expressed as mean 6 standard deviation (n = 8). The signi fi cance of the differences among groups in terms of mean is researched by ANOVA test. In the ANOVA test, Tukey method from “post-hoc ” is used to fi nd out which group reveals the difference among groups. Values in the same rows with different letters (a – e) are statistically different (p < 0.05 ). SOD: Superoxide dismutase, GSH-Px: Glutathione peroxidase, MDA: Malondialdehyde, PC: Protein carbonyl, NO: Nitric oxide, GSH: Glutathione Table 6. Serum SOD, GSH-Px activities, MDA, PC, NO, GSH levels
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354
reported that carnitine application has decreased significantly TG level in rats fed with rich fructose diet.
Based on thesefindings, HFCS consumption significantly changes total cholesterol, LDL,
TG levels in rat sera. The view that feeding with excessive HFCS negatively affects the lipid
profile has been supported once again. Group III total cholesterol, VLDL, TG levels were
found to be significant when compared with the total cholesterol, VLDL, TG levels of the
group IV and Group V groups. Therefore, we can say that L-carnitine and trans-chalcone
molecules can be sufficient candidates for correcting lipid profiles.
Previous studies have shown that high fructose consumption triggers oxidative stress and lipid peroxidation. In previous studies, high fructose consumption increased MDA levels, SOD and CAT activities decreased. However, oxidative stress has been shown to
decrease thanks to the antioxidants given in these studies (Saygin et al., 2016;Iskender et al.,
2020). In our study, the MDA level of Group III increased. L-carnitine and trans-chalcone
reduced MDA levels. According to these findings, high fructose consumption increases
oxidative stress. However, it can be interpreted that antioxidants decrease the oxidative stress caused by high fructose.
Recent studies suggest that FAS may be a therapeutic target for controlling appetite and body weight in which nutritional behavior is involved. There are studies suggesting that FAS activity correlates positively with body fat level, and this is a close connection between FAS and obesity. Loftus et al. synthesized FAS inhibitor C75. Mice were observed to have a
95% decrease in C75’s fatty acids by 14.5% intramuscular injection of C75 and an increase
of 110% in the main substrate, hepatic malonyl-CoA and weight loss. Mice were observed to have increased weight loss leading to a decrease of 95% in 14 C-acetate incorporation into fatty acids of C75 by intraperitoneal injection of C75 and an increase of 110% in hepatic malonil-CoA, the main substrate of FAS. In addition, C75 was found to accelerate fatty acid b -oxidation (Loftus et al., 2000).
In 2011,Tian et al. (2011)reported the presence of active substances that are claimed to
be FAS inhibitor in many plant species. They reported that active substances such as
Ursolic acid, EGCG, quercetin, kaempferol, morin, isorhamnetin are FAS inhibitor.Kao et al.
(2000)EGCG reported that EGCG has caused weight loss in the mice with EGCG, but they
could not reveal the mechanism clearly in their studies. Afterwards in their study, Tian et al. explained that EGCG has caused weight loss because EGCG is an inhibitor of FAS. In our
study, hepatic FAS activity of Group III has increased significantly compared to the Group I.
In our study, excessive consumption of HFCS may have accelerated fatty acid synthesis by increasing hepatic FAS activity, the lipogenic enzyme. Increased fatty acid synthesis may have led to increased TG level. However, when hepatic FAS activities of group IV and group
V are compared to hepatic FAS activity of Group II, no significance is found. We may think
that the reason why hepatic FAS activity of the Group IV and Group V has not decreased compared to Group II is due to the inadequacy of dose amount of the given L-carnitine and trans-chalcone. In a study, by increasing the dose amount of L-carnitine and trans-chalcone, the effect of L-carnitine and trans-chalcone on FAS activity can be researched.
SREBPs have been considered as targets for the treatment of metabolic diseases, as SREBPs regulate the expression of a number of enzymes necessary for the synthesis of endogenous cholesterol, fatty acids, triacylglycerol and phospholipids, and regulate lipid
homeostasis (An et al., 2020). SREBP-1c is the most important transcription factor that
regulates the expression of enzymes for fatty acid synthesis. When SREBP-1c expression is suppressed during fasting and a high carbohydrate diet is applied to animals, it increases prominently. The induction of SREBP-1c transcription causes a parallel increase in the expression of both the ER membrane-bound precursor and the nuclear form of the
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transcription factor (Davidson and Shelness, 2000).Zhang et al. (2012)reported that HFCS in mice fed with HFCS has increased hepatic SREBP-1c activation, expression of SREBP-1c target genes and has increased the two target genes, fat FAS and ACC activity of SREBP-1c.
Aragno et al. (2009)reported that SREB-1c level has increased significantly in liver tissue of
rats fed with Western type high-fat dietþ fructose. In our study, hepatic SREBP-1c level of
HFCS group has increased significantly compared to hepatic SREB-1c level of the control
group. SREBP-1c activates the transcription of multiple genes encoding enzymes responsible for the synthesis of fatty acids in cells (Brown et al., 1997).
The reason why TG level of Group III is high compared to TG level of the Group I is thought to be that HFCS consumption leads to an increase in SREB-1c expression.
Significant increase in TG and SREBP-1c levels, FAS activity of Group III compared to TG
and SREBP-1c levels, FAS activity of the Group I suggest the possibility that HFCS consumption increases lipid biosynthesis. Hepatic SREBP-1c levels of Group IV and Group
V have decreased significantly compared to Group II. We found that TG-levels of L-carnitine
and trans-chalcone have decreased significantly compared to Group II. The reason why
hepatic FAS activity of Group IV and Group V has not decreased compared to hepatic FAS activity of Group II is thought to be that L-carnitine and trans-chalcone molecules are not possibly FAS inhibitor or as mentioned earlier in the study it suggests the inadequacy of dose amounts. In the light of this information, we are on the opinion that control of SREB-1c may play an important role in feeding and decreasing the risk of metabolic diseases.
Increased evidence in recent years shows that ER stress and UPR activation may play an
important role, especially in the process of lipid metabolism (Basseri and Austin, 2012)
GRP-78 is the main regulator for ER stress (Lee, 2005;Zhu and Lee, 2015). Weight loss in people
causes ER stress indicators to be reversed in adipose and liver tissue.Gregor et al. (2009)
researched GRP-78 levels in liver and adipose tissue of 11 obese men and women before gastric bypass operation, and in their liver and adipose tissue one year after the operation. In
their study, they observed a decrease of 396 9% in the weight of the patients one year after
the operation compared to their weight before the surgery. They observed a significant
decrease in GRP-78 mRNA levels of postoperative liver and adipose tissue compared to these preoperative tissues. At the end of the study, they concluded that GRP-78 mRNA level has decreased due to weight loss and GRP-78 level of ER stress biomarkers are related to
obesity. In our study, hepatic GRP-78 level of Group III has increased significantly
compared to the Group I. A significant positive correlation is found between total cholesterol
level and hepatic GRP-78 level. Therewithal, a significant positive correlation is found for
hepatic GRP-78 weight loss results. We think that increased weight or excessive HFCS consumption may have increased GRP-78 levels. Zhang et al. reported that excessive fructose consumption has triggered hepatic ER stress and hepatic GRP-78 level of mice fed
with HFCS has increased (Zhang et al., 2012).Bhuvaneswari et al. (2014)observed that BIP, i.
e. GRP-78 level in mice fed with high-fructose fat diet (HFFD) has increased. These results support our study. Another topic of discussion is the approaches between increased oxidative stress biomarker MDA and ER stress biomarker GRP-78 levels in Group III. In our study, MDA and GRP-78 levels of Group III are found to be high compared to Group I.
Besides, a significant positive correlation is found between the MDA level and GRP-78 level
of the groups.
According to our study, oxidative stress may have triggered ER stress. Oxidative stress increases induction of cytoplasmic calcium or ROS levels in mitochondria. Mitochondrial
ROS increases ER stress response (Murphy, 2009;Dolai et al., 2011). GRP-78 level of Group
III being high compared to the Group I suggests again the relationship between oxidative stress and ER stress.
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XBP1 is the key regulator of ER stress response the lipogenic transcription factor. (Ron
and Walter, 2007). In our study, hepatic XBP-1 level of Group III has increased significantly
compared to hepatic XBP-1 level of Group I. Hepatic XBP-1 levels of Group IV and Group V
have decreased significantly compared to hepatic XBP-1 level of Group II. Excessive HFCS
consumption has increased hepatic XBP-1 level. They believe that XBP-1 protein expression has been increased in mice fed with carbohydrate and that XBP-1 is associated with critical
genes involved in fatty acid synthesis (Herrema et al., 2016). Hepatic GRP-78 and hepatic
XBP-1 levels of Group III being high compared to hepatic GRP-78 and hepatic XBP-1 levels
of the Group I group may indicate that feeding with HFCS places a burden on the liver.Liu
X et al. (2015) argue that the XBP-1 protein may be a potential therapeutic target for
pharmacological or genetic treatments. In our study, the significant decrease in hepatic
XBP-1 levels of Group IV and Group V compared to Group II, but no significant decrease in
hepatic GRP-78 levels of Group IV and Group V compared to Group II support this view. No decrease in hepatic GRP-78 levels of Group IV and Group V compared Group II forms the opinion that GRP-78 is only a marker of ER stress and cannot be a therapeutic target. However, in the light of these results, it is concluded that XBP-1 protein may be a potential therapeutic target for pharmacological or genetic treatments.
5. Conclusion
This study provides unique data on the effects of HFCS consumption on endoplasmic
reticulum stress, oxidative stress, fatty acid synthesis. In addition, somefindings support
and reinforce previous results regarding HFCS. It has been observed that groups containing HFCS in drinking water drink more liquids but the same groups consume less chow. Because rats met their daily calorie needs from HFCS. It can be concluded that consuming the drinks containing glucose syrup in daily life prevents us from eating healthy foods by
removing them from feeding withfiber. It is observed that excessive HFCS consumption has
increased lipid profile parameters TG, total cholesterol and LDL levels and oxidative stress
biomarker MDA level, ER stress biomarker GRP-78. Trans-chalcone and L-carnitine are found to have curative effects against the conditions damaging intracellular and extracellular homeostasis such as oxidative stress and ER stress. In particular, the anti-obesity feature of trans chalcone has been revealed. In addition, it can be concluded that parameters such as XBP-1, FAS and SREB-1c may be a therapeutic target for control of nutritional behavior and body weight.
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Corresponding author
Velid Unsal can be contacted at:velidunsal@gmail.com
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E
ffects of
L-carnitine and
trans-chalcone
361
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