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Moradian R, Haji Ghasem A, Rahmati S, Moradi L. Investigation of the simultaneous effect of resistance training and atorvastatin in improving nonalcoholic fatty liver disease in Wistar rats fed high high-fat/fructose diet. mljgoums 2025; 19 (3) :48-52
URL: http://mlj.goums.ac.ir/article-1-1730-en.html
URL: http://mlj.goums.ac.ir/article-1-1730-en.html
1- Department of Physical Education and Sports Sciences Central Tehran Branch, Islamic Azad University, Tehran, Iran
2- Department of Physical Education and Sports Sciences Central Tehran Branch, Islamic Azad University, Tehran, Iran ,amir.hajighasem01@gmail.com
3- Department of Physical Education, Pardis Branch, Islamic Azad University, Pardis, Iran
4- Department of Physical Education and Sports Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
2- Department of Physical Education and Sports Sciences Central Tehran Branch, Islamic Azad University, Tehran, Iran ,
3- Department of Physical Education, Pardis Branch, Islamic Azad University, Pardis, Iran
4- Department of Physical Education and Sports Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
Keywords: Non-alcoholic fatty liver disease, Resistance training, Lipids, Atorvastatin, Liver enzymes
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Results
To validate the induction of NAFLD, blood samples were randomly extracted from three rats to evaluate hepatic enzymes. In addition, their liver tissue was excised to undergo pathological examination (Figure 1). The weight of the studied groups is summarized in Table 2. The findings provided evidence that there were statistically significant variations in the average weight alterations during the 1st, 2nd, and 4th weeks among the groups. In contrast, no discernible dissimilarities were detected in the other weeks. The comparison of serum levels of triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine aminotransferase (ALT) in the study groups is shown in Table 3.
Full-Text: (88 Views)
Introduction
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and persistent liver disease that encompasses an extensive range of conditions, commencing with the relatively benign accumulation of fat in the liver, known as simple steatosis, and potentially advancing to a more severe form called non-alcoholic steatohepatitis (NASH), which is characterized by inflammation and liver cell injury, and further progressing to fibrosis, a process whereby excessive connective tissue is deposited in the liver, culminating in the development of cirrhosis, a late-stage condition characterized by extensive scarring and impaired liver function, and ultimately presenting a heightened risk for the occurrence of liver carcinoma, a malignant tumor originating from liver cells (1). As the prevalence of NAFLD continues to rise, the prevention and treatment of this disease have become increasingly important.
Regular physical activity is an effective strategy for managing NAFLD, which has been shown to improve key factors involved in the pathogenesis of the disease, such as hypertriglyceridemia, hyperglycemia, and obesity (2). Among the various types of physical activity, resistance training has gained attention for its potential benefits in reducing liver fat and improving liver function (3). Resistance training, also known as strength training or weightlifting, is a form of exercise that focuses on building and maintaining muscular strength, endurance, power, and mass. While traditionally viewed as a complement to aerobic exercise, resistance training has shown promise in improving liver health in NAFLD patients (4). In addition to reducing liver fat, RT had several positive effects on NAFLD. These effects are important for overall health and can contribute to improved metabolic function (5). Moreover, the RT had significant reductions in serum ferritin and total cholesterol levels. Lowering ferritin levels is particularly beneficial for individuals with NAFLD, as high ferritin levels have been linked to liver inflammation and fibrosis. By reducing ferritin and cholesterol levels, RT may help mitigate the progression of NAFLD (2,6). There are multiple therapeutic interventions available to address this complication. One approach involves the administration of ATO, a prescribed medication intended for the treatment of this particular ailment. ATO, a statin medication, may cause liver complications, increased cell apoptosis, and even mortality when used in high doses or over prolonged periods. Furthermore, ATO effectively reduces levels of cholesterol, triglyceride (TG), and low-density lipoprotein-C (LDL-C), while simultaneously elevating high-density lipoprotein-C (HDL-C) levels within the bloodstream. In addition, ATO exhibits antioxidative, anti-apoptotic, and anti-inflammatory attributes (7). The mechanism of ATO involves protein prenylation inhibition, mitochondrial dysfunction, oxidative stress, and damage in various cell types. ATO also affects fatty acid metabolism, oxidative stress, and mitochondrial dysfunction in the kidneys, leading to nephrotoxicity (8). Recently, a multitude of investigations have unveiled that the administration of ATO exhibits efficacy and safety in the management of individuals afflicted with NAFLD or NASH accompanied by hyperlipidemia (9). ATO exhibits dual effects in patients, as it not only reduces liver transaminase levels but also effectively suppresses hepatic steatosis (10). This study aimed to determine the simultaneous effects of RT and ATO on improving NAFLD in rats fed HFFD.
Methods
Twenty-one male Wistar rats (200-250 gr) were obtained from Shahid Mirghani Research Institute (Golestan, Iran). The animals were provided unrestricted access to both feed and water throughout the entire experiment and were housed in a controlled facility with a 12-hour dark/light cycle and a temperature ranging from 20 to 24 °C. A period of one week was allocated for the rats to adapt to their new surroundings and familiarize themselves with their living conditions. Subsequent to this acclimation period, the rats were exposed to the induction of NAFLD in accordance with the established protocol developed by Eslami et al. (11). After a period of 15 weeks, NAFLD had been induced in the rats by assessment of biochemical and histopathological findings. The animals were then divided into three groups: 1. NAFLD (Control), 2. NAFLD+ RT+ ATO, and 3. NAFLD + RT. The interventions, including ATO administration at a dosage of 2 mg/kg/day (12) and RT, were maintained for eight weeks. The rats were rendered unconscious through the administration of ketamine (50 mg/kg) and xylazine (5 mg/kg, Merck, Germany) via intraperitoneal injection, thereby inducing anesthesia (13). Standard enzymatic techniques were utilized for the evaluation of the aminotransferases and alkaline phosphatase (ALP), and an auto-analyzer (BT-3500, Biotecnica Instruments, Italy) was employed for the measurement of TG, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels (Pars Azmoon, Tehran, Iran).
In the 23rd week, the rats were euthanized. Following the acquisition of blood samples, the livers were promptly excised and rinsed with normal saline. Subsequently, liver tissue samples were obtained through incisions and preserved in a 10% buffered formaldehyde solution. These samples were then embedded in paraffin for hematoxylin-eosin (H and E) staining and grading of NAFLD. The period of adaptation involved engaging in climbing sessions on a wooden ladder that measured 110 cm in height and 18 cm in width, featuring an incline of 80 degrees. Positioned at the ladder's summit, there existed a designated rest area where the animals were stationed for two minutes before embarking on the subsequent repetition. Within this timeframe, the animals acquired the skill of ascending the ladder using stimuli being applied to their tails utilizing forceps. Upon the fulfillment of the adaptation phase, which entailed a maximum of six successive sessions spanning a week, the training protocol no longer necessitated the presence of any stimuli. The training sessions consistently occurred in the afternoon, transpiring five times per week over eight weeks, accumulating a total of 40 sessions. Each training session involved completing the task of climbing 15 times (14). The protocol of RT is mentioned in Table 1.
The sample size was determined using G*Power software. We considered significance level (α) at 0.05 and power (1-β) at %80 to determine sample size. The determination of the data distribution was accomplished through the utilization of the Shapiro-Wilk test, while the evaluation of the equality of variances was performed using Levene's test. Moreover, for group comparisons, we used One-Way ANOVA and Tukey post hoc test. The execution of this analysis was carried out utilizing version 16 of the SPSS software, with the significance level set at P ≤0.05. The investigation was conducted in compliance with the guidelines outlined in the publication "Guide for the Care and Use of Laboratory Animals" issued by the National Institutes of Health (NIH publication No. 85-23, revised 1996). The research protocol was approved by the Ethics Committee of the Local Institution (IR.SSRC.REC.1402.121).
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and persistent liver disease that encompasses an extensive range of conditions, commencing with the relatively benign accumulation of fat in the liver, known as simple steatosis, and potentially advancing to a more severe form called non-alcoholic steatohepatitis (NASH), which is characterized by inflammation and liver cell injury, and further progressing to fibrosis, a process whereby excessive connective tissue is deposited in the liver, culminating in the development of cirrhosis, a late-stage condition characterized by extensive scarring and impaired liver function, and ultimately presenting a heightened risk for the occurrence of liver carcinoma, a malignant tumor originating from liver cells (1). As the prevalence of NAFLD continues to rise, the prevention and treatment of this disease have become increasingly important.
Regular physical activity is an effective strategy for managing NAFLD, which has been shown to improve key factors involved in the pathogenesis of the disease, such as hypertriglyceridemia, hyperglycemia, and obesity (2). Among the various types of physical activity, resistance training has gained attention for its potential benefits in reducing liver fat and improving liver function (3). Resistance training, also known as strength training or weightlifting, is a form of exercise that focuses on building and maintaining muscular strength, endurance, power, and mass. While traditionally viewed as a complement to aerobic exercise, resistance training has shown promise in improving liver health in NAFLD patients (4). In addition to reducing liver fat, RT had several positive effects on NAFLD. These effects are important for overall health and can contribute to improved metabolic function (5). Moreover, the RT had significant reductions in serum ferritin and total cholesterol levels. Lowering ferritin levels is particularly beneficial for individuals with NAFLD, as high ferritin levels have been linked to liver inflammation and fibrosis. By reducing ferritin and cholesterol levels, RT may help mitigate the progression of NAFLD (2,6). There are multiple therapeutic interventions available to address this complication. One approach involves the administration of ATO, a prescribed medication intended for the treatment of this particular ailment. ATO, a statin medication, may cause liver complications, increased cell apoptosis, and even mortality when used in high doses or over prolonged periods. Furthermore, ATO effectively reduces levels of cholesterol, triglyceride (TG), and low-density lipoprotein-C (LDL-C), while simultaneously elevating high-density lipoprotein-C (HDL-C) levels within the bloodstream. In addition, ATO exhibits antioxidative, anti-apoptotic, and anti-inflammatory attributes (7). The mechanism of ATO involves protein prenylation inhibition, mitochondrial dysfunction, oxidative stress, and damage in various cell types. ATO also affects fatty acid metabolism, oxidative stress, and mitochondrial dysfunction in the kidneys, leading to nephrotoxicity (8). Recently, a multitude of investigations have unveiled that the administration of ATO exhibits efficacy and safety in the management of individuals afflicted with NAFLD or NASH accompanied by hyperlipidemia (9). ATO exhibits dual effects in patients, as it not only reduces liver transaminase levels but also effectively suppresses hepatic steatosis (10). This study aimed to determine the simultaneous effects of RT and ATO on improving NAFLD in rats fed HFFD.
Methods
Twenty-one male Wistar rats (200-250 gr) were obtained from Shahid Mirghani Research Institute (Golestan, Iran). The animals were provided unrestricted access to both feed and water throughout the entire experiment and were housed in a controlled facility with a 12-hour dark/light cycle and a temperature ranging from 20 to 24 °C. A period of one week was allocated for the rats to adapt to their new surroundings and familiarize themselves with their living conditions. Subsequent to this acclimation period, the rats were exposed to the induction of NAFLD in accordance with the established protocol developed by Eslami et al. (11). After a period of 15 weeks, NAFLD had been induced in the rats by assessment of biochemical and histopathological findings. The animals were then divided into three groups: 1. NAFLD (Control), 2. NAFLD+ RT+ ATO, and 3. NAFLD + RT. The interventions, including ATO administration at a dosage of 2 mg/kg/day (12) and RT, were maintained for eight weeks. The rats were rendered unconscious through the administration of ketamine (50 mg/kg) and xylazine (5 mg/kg, Merck, Germany) via intraperitoneal injection, thereby inducing anesthesia (13). Standard enzymatic techniques were utilized for the evaluation of the aminotransferases and alkaline phosphatase (ALP), and an auto-analyzer (BT-3500, Biotecnica Instruments, Italy) was employed for the measurement of TG, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels (Pars Azmoon, Tehran, Iran).
In the 23rd week, the rats were euthanized. Following the acquisition of blood samples, the livers were promptly excised and rinsed with normal saline. Subsequently, liver tissue samples were obtained through incisions and preserved in a 10% buffered formaldehyde solution. These samples were then embedded in paraffin for hematoxylin-eosin (H and E) staining and grading of NAFLD. The period of adaptation involved engaging in climbing sessions on a wooden ladder that measured 110 cm in height and 18 cm in width, featuring an incline of 80 degrees. Positioned at the ladder's summit, there existed a designated rest area where the animals were stationed for two minutes before embarking on the subsequent repetition. Within this timeframe, the animals acquired the skill of ascending the ladder using stimuli being applied to their tails utilizing forceps. Upon the fulfillment of the adaptation phase, which entailed a maximum of six successive sessions spanning a week, the training protocol no longer necessitated the presence of any stimuli. The training sessions consistently occurred in the afternoon, transpiring five times per week over eight weeks, accumulating a total of 40 sessions. Each training session involved completing the task of climbing 15 times (14). The protocol of RT is mentioned in Table 1.
The sample size was determined using G*Power software. We considered significance level (α) at 0.05 and power (1-β) at %80 to determine sample size. The determination of the data distribution was accomplished through the utilization of the Shapiro-Wilk test, while the evaluation of the equality of variances was performed using Levene's test. Moreover, for group comparisons, we used One-Way ANOVA and Tukey post hoc test. The execution of this analysis was carried out utilizing version 16 of the SPSS software, with the significance level set at P ≤0.05. The investigation was conducted in compliance with the guidelines outlined in the publication "Guide for the Care and Use of Laboratory Animals" issued by the National Institutes of Health (NIH publication No. 85-23, revised 1996). The research protocol was approved by the Ethics Committee of the Local Institution (IR.SSRC.REC.1402.121).
|
Table 1. The protocol of resistance training
.PNG) |
Results
To validate the induction of NAFLD, blood samples were randomly extracted from three rats to evaluate hepatic enzymes. In addition, their liver tissue was excised to undergo pathological examination (Figure 1). The weight of the studied groups is summarized in Table 2. The findings provided evidence that there were statistically significant variations in the average weight alterations during the 1st, 2nd, and 4th weeks among the groups. In contrast, no discernible dissimilarities were detected in the other weeks. The comparison of serum levels of triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine aminotransferase (ALT) in the study groups is shown in Table 3.
.PNG) Figure 1. (A) Serum ALT levels, (B) Serum AST levels, (C) H and E staining of liver tissues in three samples. ALT: Alanine Aminotransferase, AST: Aspartate Aminotransferase, H and E: Hematoxylin and Eosin. |
|
Table 2. Mean and standard deviation (SD) of weight (gr)
.PNG) * Significant: P ≤ 0.05 NAFLD: Non-Alcoholic Fatty Liver Disease, RT: Resistance Training, ATO: Atorvastatin. Table 3. Mean of biochemical indicators .PNG) * Significant: P ≤ 0.05 NAFLD: Non- Alcoholic Fatty Liver Disease, RT: Resistance Training, ATO: Atorvastatin. TG: Triglycerides, LDL: Low-Density Lipoprotein, HDL: High-Density Lipoprotein, ALT: Alanine Aminotransferase, AST: Aspartate Aminotransferase, ALP: Alkaline Phosphatase. Table 4. Levene's test to assess the homogeneity of weight variance .PNG) Table 5. Levene's test to assess the homogeneity of lipid and liver enzymes variance .PNG) |
Additionally, the results of Levene's test are shown in Tables 4 and 5.
The results of the Tukey post hoc test indicate a significant dissimilarity in the TG levels among the study groups (P=0.000). Similarly, LDL levels (P=0.019) showed significant differences. The analysis of liver enzymes further substantiated these findings, highlighting a significant difference in the ALT (P=0.017), AST (P=0.000), and ALP (P=0.006) levels across the study groups (Table 4). The findings of the group comparison revealed that TG (P=0.000), LDL (P= 0.001), AST (P= 0.002), and ALP (P= 0.10) levels decreased in NAFLD + RT group compared to the NAFLD group. The NAFLD + RT+ ATO group exhibited reduced TG (P= 0.000), AST (P= 0.001), ALT (P=0.021), and ALP (P= 0.015) levels in comparison to the NAFLD group. Although the lipid indices and liver enzymes have decreased compared to the control group, the difference between the intervention groups was not significant. This suggests that RT not only reduced lipid profile but also contributed to the improved liver enzymes in NAFLD.
Discussion
Atorvastatin (ATO) administration alone can improve lipid profile in patients with dyslipidemia. Furthermore, combining ATO with other interventions can enhance its therapeutic efficacy in managing dyslipidemia. This combination can lead to improvements in insulin resistance, endothelial function, oxidative stress markers, lipid profile, and metabolic control. Also, RT has shown promise in improving NAFLD. One study conducted on male rats with NAFLD showed that RT significantly improved liver fat content compared to other exercise modalities (15). The present study examined the simultaneous effect of RT and ATO on improving NAFLD in rats fed HFFD.
A randomized clinical trial conducted by Zelber-Sagi et al. investigated the effect of RT on NAFLD patients. The study enrolled patients without secondary liver diseases, such as viral hepatitis or excessive alcohol consumption, and randomly assigned them to either an RT group or a control group that performed home stretching exercises. The RT program consisted of exercises such as leg press, chest press, seated rowing, and latissimus pull down, with 8-12 repetitions and three sets for each exercise, performed three times a week for a total duration of 40 minutes (2). Oh et al. reported that high-intensity aerobic training improved hepatic fat contents in NAFLD patients (16). Exercise therapy, a widely recognized and well-established approach, has proven to be highly efficacious in addressing a multitude of metabolism-associated diseases. The incorporation of both resistance and aerobic exercises in a comprehensive treatment plan has been deemed more logical and fruitful in the realm of clinical practice. This combined exercise regimen has demonstrated remarkable success in yielding positive outcomes (17). Pekkala et al. demonstrated that both high-intensity interval training and moderate-intensity training showed an equivalent level of efficacy in mitigating the weight gain caused by a high-fat diet in rats (18). In a study conducted by Eslami et al., it was demonstrated that the implementation of aerobic exercise over a duration of 12 weeks resulted in a noticeable reduction in the expression of the mitogen-activated protein kinase (MAPK) P38 gene within the subcutaneous adipose tissue of rats that were fed high-fat diet. This finding is of great significance as it highlights the potential of aerobic exercise in modulating the genetic factors involved in adipose tissue metabolism, especially targeting the MAPK P38 gene. The implications of this study extend beyond the realm of animal models, as it provides valuable insights into the potential therapeutic applications of exercise interventions in combating the detrimental effects of high-fat diet on adipose tissue function (19,20). Also, it was demonstrated that endurance training exhibited a significant reduction in anthropometric indices subsequent to a duration of 12 weeks in obese rats (21) consistent with the findings of Mirghani et al. study (22).
An exercise regimen that focuses on aerobic activities over a span of 24 weeks was implemented in a group of postmenopausal women diagnosed with NAFLD. The results of this program revealed significant enhancements in certain parameters, including a reduction in waist circumference, an increase in HDL-C levels, and an improvement in cardiopulmonary performance. These positive outcomes potentially contribute to the amelioration of cardiovascular risk factors within this specific demographic (23). Moderate-intensity aerobic training refers to physical activities that increase heart rate and breathing but can still be sustained for a prolonged period without exhaustion. Resistance training involves repetitive exercises that use resistance or weights to build strength and endurance. When combined with dietary modification, which involves making changes to one's eating habits and food choices, these interventions have been found to have an equal level of effectiveness in the reduction of intrahepatic fat, which is the accumulation of fat within the liver, and improvement of the underlying insulin resistance. Insulin resistance is a condition where the body's cells do not respond properly to insulin. These effects are observed among patients who have non-alcoholic fatty liver disease (NAFLD), a condition characterized by the buildup of fat in the liver that is not caused by excessive alcohol consumption (24). In addition, it has been concluded that the implementation of concurrent training has the ability to impede the reduction of serum HDL levels that may occur as a result of engaging in strength training among young males (25,26).
Based on the findings of this study and previous research, RT can be considered an effective and complementary approach to managing NAFLD. The American Heart Association and the American College of Sports Medicine recommend incorporating RT at least twice a week in addition to aerobic exercise for overall health benefits. For NAFLD patients, RT can serve as an alternative or complementary form of exercise, especially for those who may have physical limitations or low motivation to engage in aerobic activities. Before starting an RT program, NAFLD patients need to consult with their healthcare providers and undergo a thorough evaluation to ensure they can safely engage in this form of exercise. Working with a certified fitness professional or exercise physiologist can also help design an appropriate RT program tailored to individual needs and goals. Studies have also investigated the effects of ATO on the context of NAFLD. Studies conducted on a rat model of NAFLD reported that ATO treatment improved lipid profiles and liver function. Triglyceride, cholesterol, and liver enzyme levels were significantly reduced in the group receiving ATO compared to the control group. Also, ATO was found to effectively control liver enzymes and improve the lipid profile in rats with NAFLD (7,13). Ji et al. found that ATO treatment was highly effective in improving hyperlipidemia associated with NAFLD and also in inhibiting liver steatosis. These beneficial effects were observed in conjunction with the modulation of genes that are involved in the regulation of lipid metabolism. Furthermore, the addition of ATO to dietary control interventions was found to greatly enhance their efficacy in reducing the levels of serum total cholesterol and LDL-C; however, it did not significantly affect TG levels, free fatty acid levels, or hepatic steatosis in rats with high-fat diet-induced fatty liver and hyperlipidemia (27).
RT and ATO have been studied individually for their effects on NAFLD; however, there is limited research on their simultaneous effect. The current literature suggests that exercise, such as RT, can improve liver enzymes, body composition, and lipid profiles in individuals with NAFLD. Additionally, aerobic exercise and RT have both been shown to reduce intrahepatic fat in patients with NAFLD (28). Furthermore, acceleration training, a form of exercise that increases gravitational acceleration with vibration, has been found to be effective in reducing hepatic fat content and improving liver function in obese patients with NAFLD (29). However, there is limited research specifically investigating the simultaneous effect of RT and ATO on improving NAFLD. Conducting such research could provide valuable insights into the potential synergistic effects of these interventions on NAFLD management.
Conclusion
Resistance training (RT) and atorvastatin (ATO) have been studied separately for their effects on NAFLD; however, there is no specific information available on their simultaneous effect. Studies have shown that RT can improve liver enzymes, hepatic fat, and histologic markers in NAFLD. On the other hand, ATO is a medication used to lower cholesterol levels and has been shown to improve liver function in NAFLD patients. However, there is no direct evidence on the simultaneous effect of RT and ATO on improving NAFLD. Further research is needed to determine the combined effect of these interventions on NAFLD.
Acknowledgement
The authors would like to thank the staff of Shahid Mirghani Research Institute in Gorgan, Golestan.
Funding sources
None.
Ethical statement
The research protocol was approved by the Ethics Committee of the Local Institution (IR.SSRC.REC.1402.121).
Conflicts of interest
The authors declare that there is no conflict of interest regarding the publication of this article.
Author contributions
RM: Preparation of manuscript, analyzed and interpreted the data. AH: Conception and design, overall scientific management. SR and LM: Conception and design. All authors read and approved the final manuscript.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
The results of the Tukey post hoc test indicate a significant dissimilarity in the TG levels among the study groups (P=0.000). Similarly, LDL levels (P=0.019) showed significant differences. The analysis of liver enzymes further substantiated these findings, highlighting a significant difference in the ALT (P=0.017), AST (P=0.000), and ALP (P=0.006) levels across the study groups (Table 4). The findings of the group comparison revealed that TG (P=0.000), LDL (P= 0.001), AST (P= 0.002), and ALP (P= 0.10) levels decreased in NAFLD + RT group compared to the NAFLD group. The NAFLD + RT+ ATO group exhibited reduced TG (P= 0.000), AST (P= 0.001), ALT (P=0.021), and ALP (P= 0.015) levels in comparison to the NAFLD group. Although the lipid indices and liver enzymes have decreased compared to the control group, the difference between the intervention groups was not significant. This suggests that RT not only reduced lipid profile but also contributed to the improved liver enzymes in NAFLD.
Discussion
Atorvastatin (ATO) administration alone can improve lipid profile in patients with dyslipidemia. Furthermore, combining ATO with other interventions can enhance its therapeutic efficacy in managing dyslipidemia. This combination can lead to improvements in insulin resistance, endothelial function, oxidative stress markers, lipid profile, and metabolic control. Also, RT has shown promise in improving NAFLD. One study conducted on male rats with NAFLD showed that RT significantly improved liver fat content compared to other exercise modalities (15). The present study examined the simultaneous effect of RT and ATO on improving NAFLD in rats fed HFFD.
A randomized clinical trial conducted by Zelber-Sagi et al. investigated the effect of RT on NAFLD patients. The study enrolled patients without secondary liver diseases, such as viral hepatitis or excessive alcohol consumption, and randomly assigned them to either an RT group or a control group that performed home stretching exercises. The RT program consisted of exercises such as leg press, chest press, seated rowing, and latissimus pull down, with 8-12 repetitions and three sets for each exercise, performed three times a week for a total duration of 40 minutes (2). Oh et al. reported that high-intensity aerobic training improved hepatic fat contents in NAFLD patients (16). Exercise therapy, a widely recognized and well-established approach, has proven to be highly efficacious in addressing a multitude of metabolism-associated diseases. The incorporation of both resistance and aerobic exercises in a comprehensive treatment plan has been deemed more logical and fruitful in the realm of clinical practice. This combined exercise regimen has demonstrated remarkable success in yielding positive outcomes (17). Pekkala et al. demonstrated that both high-intensity interval training and moderate-intensity training showed an equivalent level of efficacy in mitigating the weight gain caused by a high-fat diet in rats (18). In a study conducted by Eslami et al., it was demonstrated that the implementation of aerobic exercise over a duration of 12 weeks resulted in a noticeable reduction in the expression of the mitogen-activated protein kinase (MAPK) P38 gene within the subcutaneous adipose tissue of rats that were fed high-fat diet. This finding is of great significance as it highlights the potential of aerobic exercise in modulating the genetic factors involved in adipose tissue metabolism, especially targeting the MAPK P38 gene. The implications of this study extend beyond the realm of animal models, as it provides valuable insights into the potential therapeutic applications of exercise interventions in combating the detrimental effects of high-fat diet on adipose tissue function (19,20). Also, it was demonstrated that endurance training exhibited a significant reduction in anthropometric indices subsequent to a duration of 12 weeks in obese rats (21) consistent with the findings of Mirghani et al. study (22).
An exercise regimen that focuses on aerobic activities over a span of 24 weeks was implemented in a group of postmenopausal women diagnosed with NAFLD. The results of this program revealed significant enhancements in certain parameters, including a reduction in waist circumference, an increase in HDL-C levels, and an improvement in cardiopulmonary performance. These positive outcomes potentially contribute to the amelioration of cardiovascular risk factors within this specific demographic (23). Moderate-intensity aerobic training refers to physical activities that increase heart rate and breathing but can still be sustained for a prolonged period without exhaustion. Resistance training involves repetitive exercises that use resistance or weights to build strength and endurance. When combined with dietary modification, which involves making changes to one's eating habits and food choices, these interventions have been found to have an equal level of effectiveness in the reduction of intrahepatic fat, which is the accumulation of fat within the liver, and improvement of the underlying insulin resistance. Insulin resistance is a condition where the body's cells do not respond properly to insulin. These effects are observed among patients who have non-alcoholic fatty liver disease (NAFLD), a condition characterized by the buildup of fat in the liver that is not caused by excessive alcohol consumption (24). In addition, it has been concluded that the implementation of concurrent training has the ability to impede the reduction of serum HDL levels that may occur as a result of engaging in strength training among young males (25,26).
Based on the findings of this study and previous research, RT can be considered an effective and complementary approach to managing NAFLD. The American Heart Association and the American College of Sports Medicine recommend incorporating RT at least twice a week in addition to aerobic exercise for overall health benefits. For NAFLD patients, RT can serve as an alternative or complementary form of exercise, especially for those who may have physical limitations or low motivation to engage in aerobic activities. Before starting an RT program, NAFLD patients need to consult with their healthcare providers and undergo a thorough evaluation to ensure they can safely engage in this form of exercise. Working with a certified fitness professional or exercise physiologist can also help design an appropriate RT program tailored to individual needs and goals. Studies have also investigated the effects of ATO on the context of NAFLD. Studies conducted on a rat model of NAFLD reported that ATO treatment improved lipid profiles and liver function. Triglyceride, cholesterol, and liver enzyme levels were significantly reduced in the group receiving ATO compared to the control group. Also, ATO was found to effectively control liver enzymes and improve the lipid profile in rats with NAFLD (7,13). Ji et al. found that ATO treatment was highly effective in improving hyperlipidemia associated with NAFLD and also in inhibiting liver steatosis. These beneficial effects were observed in conjunction with the modulation of genes that are involved in the regulation of lipid metabolism. Furthermore, the addition of ATO to dietary control interventions was found to greatly enhance their efficacy in reducing the levels of serum total cholesterol and LDL-C; however, it did not significantly affect TG levels, free fatty acid levels, or hepatic steatosis in rats with high-fat diet-induced fatty liver and hyperlipidemia (27).
RT and ATO have been studied individually for their effects on NAFLD; however, there is limited research on their simultaneous effect. The current literature suggests that exercise, such as RT, can improve liver enzymes, body composition, and lipid profiles in individuals with NAFLD. Additionally, aerobic exercise and RT have both been shown to reduce intrahepatic fat in patients with NAFLD (28). Furthermore, acceleration training, a form of exercise that increases gravitational acceleration with vibration, has been found to be effective in reducing hepatic fat content and improving liver function in obese patients with NAFLD (29). However, there is limited research specifically investigating the simultaneous effect of RT and ATO on improving NAFLD. Conducting such research could provide valuable insights into the potential synergistic effects of these interventions on NAFLD management.
Conclusion
Resistance training (RT) and atorvastatin (ATO) have been studied separately for their effects on NAFLD; however, there is no specific information available on their simultaneous effect. Studies have shown that RT can improve liver enzymes, hepatic fat, and histologic markers in NAFLD. On the other hand, ATO is a medication used to lower cholesterol levels and has been shown to improve liver function in NAFLD patients. However, there is no direct evidence on the simultaneous effect of RT and ATO on improving NAFLD. Further research is needed to determine the combined effect of these interventions on NAFLD.
Acknowledgement
The authors would like to thank the staff of Shahid Mirghani Research Institute in Gorgan, Golestan.
Funding sources
None.
Ethical statement
The research protocol was approved by the Ethics Committee of the Local Institution (IR.SSRC.REC.1402.121).
Conflicts of interest
The authors declare that there is no conflict of interest regarding the publication of this article.
Author contributions
RM: Preparation of manuscript, analyzed and interpreted the data. AH: Conception and design, overall scientific management. SR and LM: Conception and design. All authors read and approved the final manuscript.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Research Article: Research Article |
Subject:
Sport Physiology
Received: 2023/10/8 | Accepted: 2024/01/8 | Published: 2025/06/28 | ePublished: 2025/06/28
Received: 2023/10/8 | Accepted: 2024/01/8 | Published: 2025/06/28 | ePublished: 2025/06/28
References
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