Author Affiliations: Departments of Anatomy (Guo R, Liong EC, So KF and Tipoe GL) and Physiology (Fung ML), Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

Corresponding Author: George L Tipoe, MD, PhD, Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China (Tel: +852-39179185; Fax: +852-28170857; Email: tgeorge@hku.hk)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60355-1

Published online March 18, 2015.

 

 

Contributors: GR wrote the main body of the manuscript. TGL provided advice and edited the manuscript. All authors contributed to the design, scientific input and discussion of the manuscript. TGL is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) refers to any fatty liver disease that is not due to excessive use of alcohol. NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance. Aerobic exercise is shown to improve NAFLD. This review aimed to evaluate the molecular mechanisms involved in the beneficial effects of aerobic exercise on NAFLD.

 

DATA SOURCE: We searched articles in English on the role of aerobic exercise in NAFLD therapy in PubMed.

 

RESULTS: The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include: (i) reducing intrahepatic fat content by down-regulating sterol regulatory element-binding protein-1c and up-regulating peroxisome proliferator-activated receptor γ expression levels; (ii) decreasing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; (iii) ameliorating hepatic inflammation via the inhibition of pro-inflammatory mediators such as tumor necrosis factor-alpha and interleukin-1 beta; (iv) attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and (v) inducing hepato-protective autophagy.

 

CONCLUSION: Aerobic exercise, via different mechanisms, significantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

 

(Hepatobiliary Pancreat Dis Int 2015;14:139-144)

 

KEY WORDS: non-alcoholic fatty liver disease; chronic aerobic exercise; oxidative stress; inflammation; apoptosis; autophagy

Non-alcoholic fatty liver disease (NAFLD) consists of a series of disease activity manifesting from hepatic steatosis to non-alcoholic steatohepatitis (NASH), finally resulting in cirrhosis and in some cases hepatocelluar carcinoma. In hepatic steatosis, triglyceride fat is accumulated in lipid droplets formed in the cytoplasm of hepatocytes, which ultimately leads to liver enlargement. Steatosis alone is regarded as the earliest stage of NAFLD and exhibits a reversible condition.^[1] The conversion from steatosis to NASH involves an extreme stage in which inflammation is generated and cellular damage takes place with concurrent fat accumulation in the liver. In NASH, hepatocytes are damaged by hyperinsulinemia, adipose inflammation and hypoadiponectinemia.^[2] Because of the deteriorative effect of NAFLD, it is imperative to take effective measures to attenuate NAFLD-induced injury.

 

Exercise and physical activity fall into three basic categories: (i) aerobic activities, such as walking and jogging, which are repetitive, rigorous, rhythmic, and involve large muscles (like the arms and thighs). Aerobic is translated as "with oxygen", therefore this exercise works the circulatory system; (ii) resistance exercise, which utilizes resistance to muscular contraction, can help to build the strength, anaerobic endurance and size of skeletal muscles; (iii) flexibility training, which keeps the body flexible, relaxes muscles, and protects them from physical injury. Yoga is among the best stretching exercises known to man.^[3]

 

Aerobic exercise is considered as a beneficial modifier for the health enhancement of multiple metabolic syndromes. Numerous studies^[4-9] have stressed that the increased hepatic benefit can be achieved by proper and regular chronic aerobic activity. It is highly supported by both American Gastroenterological Association and American Association for the Study of Liver Diseases that chronic aerobic exercise is a major component and plays a fundamental role in the treatment for NAFLD.^[4] Keating et al^[5] also reported that chronic physical interventions decreased hepatic lipid accumulation without weight loss, indicating that chronic exercise could be a therapeutic approach, and assessment of exercise levels and exercise prescription should be routine in NAFLD.

 

Even though some achievements have been made to investigate the beneficial effect of chronic physical exercise on NAFLD, there is still lack of information about the underlying molecular mechanisms of the positive effects of aerobic exercise. Therefore, we systematically reviewed the essential role of regular aerobic exercise in the treatment of NAFLD, with emphasis on the possible mechanisms related to its beneficial effects.

 

 

The crosslink between exercise and intrinsic hepatic effects involves β-oxidation and lipogenesis. Emerging evidence indicates that exercise could regulate hepatic lipid metabolism by modulating hepatic β-oxidation and lipogenesis. The activity of β-oxidation is significantly enhanced in the muscle of BALB/c mice which swam in a pool twice a week in a 10-week period when compared with the non-exercise control group, suggesting that beneficial effect of exercise is accompanied by the stimulation of fatty acid oxidation.^[6] While investigating the relationship between exercise and lipogenesis, Johnson et al^[7] found that physical activity is able to sharply lower liver fat content in individuals who undergo 3-month energy restriction and 150-minute aerobic exercise per week by reducing hepatic lipogenesis. The result indicates that the possibility of ameliorating NAFLD by altering the behavior of physical activity. In addition, hepatic steatosis is highly associated with the dysregulation of sterol regulatory element-binding protein-1c (SREBP-1c), a transcription factor that regulates genes which enhance triglyceride synthesis, with associated reductions in hepatic capacity for fatty acid oxidation. Cintra et al^[8] reported that SREBP-1c expression is significantly increased in mice fed with high fat diet for two months; physical exercise significantly decreases the SREBP-1c expression in these mice, suggesting that physical training could be regarded as a fundamental non-pharmacological treatment for fatty liver diseases. Petridou et al^[9] also observed that hepatic protein expression and DNA binding activity of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor protein transcription factor regulating lipid metabolism, are significantly enhanced in rat liver by aerobic exercise. Overexpression of PPARγ also inhibits the progression of hepatic steatosis in mouse models, which may be ascribed to enhanced insulin sensitivity in adipose tissue and skeletal muscle, leading to the decreased free fatty acid deposition in the liver.^[10] This finding suggests that aerobic exercise can attenuate NAFLD via the regulation of PPARγ. Thus, the results indicate that exercise can ameliorate NAFLD by down-regulating SREBP-1c and up-regulating PPARγ expression and activities.

 

 

There is a close relationship between oxidative stress and the severity of NASH. This relationship partly accounts for the development of NAFLD. When oxidative stress occurs in NAFLD, two general products are often excessively generated: reactive oxygen species (ROS) and reactive nitrogen species (RNS). Currently, it is clear that the excessive amount of ROS and RNS is responsible for the induction of pathological processes known as oxidative stress.^{[11, 12]} The up-regulation of ROS/RNS level is often considered as an activator which accelerates the development of NAFLD under oxidative condition. On the other hand, oxidative stress in NASH down-regulates the expression levels of endogenous antioxidant enzymes such as catalase which decomposes hydrogen peroxide to water and oxygen,^[13] and glutathione peroxidase (GPx) which reduces free hydrogen peroxide.^[14]

 

Chronic physical exercise itself can be considered to produce an antioxidant effect. Salminen and Vihko^[15] reported that chronic physical training protects the mouse liver from oxidative damage by up-regulating antioxidant enzymes such as superoxide dismutase (SOD) and GPx. Similarly, chronic exercise also up-regulates the expression levels of SOD-1 and GPx, which function as redox balancers in aging rats subjected to a rodent exercise treadmill, indicating that chronic exercise has antioxidant effects on counteracting oxidative stress at the early stage of aging,^[16] as well as enhancing SOD in db/db mice.^[17] Gomez-Cabrera et al^[18] suggested that physical intervention firstly activates mitogen-activated protein kinase, which in turn induces the NF-κB pathway and finally enhances the expression of antioxidant enzymes related to the defense mechanism against ROS and an adaptation to exercise. The evidence provided above indicate that exercise attenuates the oxidative damage triggered by NAFLD partly through enhancing the antioxidant enzyme level and regulating ROS level, resulting in the induction of downstream signaling pathways that offered the beneficial effects on cells.

 

 

Hepatic inflammation, another major event in NAFLD, is also a key transitional event that progresses from a simple steatosis to NASH. However, its mechanisms are obscure. In general, high fat diet induced NAFLD leads to hepatic inflammation by enhancing the expression of pro-inflammatory mediators such as TNF-α and IL-1β.^[19-21] Both pre-clinical studies and clinical trials demonstrated that physical exercise ameliorates hepatic inflammation through down-regulation of the pro-inflammatory mediators. In contrast, physical inactivity causes accumulation of visceral fat and consequently activates the inflammatory pathways, which ultimately enhances the probability of developing NAFLD. The anti-inflammatory characteristics of physical activities have been investigated in the past decades.^[22-24] Vieira et al^[25] reported that chronic exercise down-regulates the expression of TNF-α mRNA in the adipose tissue of obese mice. Moreover, physical training also significantly reduces hepatic expression of TNF-α mRNA in C57BL/6 mice fed with a high fat diet.^[26] Kawanishi et al^[27] found that chronic training suppresses chemokines and adhesion molecules in a high fat diet induced NASH mice model, decreases hepatic inflammatory macrophage infiltration and attenuates fatty liver. However, even though the beneficial properties of exercise are well known, the mechanism of its anti-inflammatory effect is still poorly understood and remains a large area for future investigation.

 

 

Apoptosis is a process of programmed cell death which leads to morphological changes and cell death including blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation.^[28] The occurrence of apoptosis in hepatocytes is often seen in NAFLD patients and experimental animal models.^[29] As a result, the inhibition of hepatocyte apoptosis serves as an important strategy in the treatment of NAFLD.

Exercise has been shown to effectively attenuate apoptosis in animal models and clinical trials. Luo et al^[30] demonstrated that chronic resistance exercise reduces the level of cytochrome C released from the mitochondria to the cytosol as well as the expression level of cleaved caspase-3 in aged rats, suggesting that exercise inhibits mitochondria-dependent apoptosis. Meanwhile, Kim et al^[31] also observed that treadmill exercise reduces diabetes-triggered apoptosis by enhancing the p-AKT expression level in diabetic rats. Additionally, it has been shown that hepatocyte apoptotic markers are diminished by treadmill walking in obese individuals with NAFLD mainly through its antioxidant activity and enhancing insulin sensitivity.^[32] Therefore, exercise exerts very positive effect on NAFLD partially by decreasing hepatocyte apoptosis in fatty liver.

 

 

Autophagy is a cellular process of degradation of intracellular components to recycle cellular waste and maintains energy balance under starvation. In this process, cytosolic proteins and organelles are sequestered to form autophagosome which ultimately fuses with lysosome to degrade the cellular components.^[33-35] Autophagy plays an important role in regulating intracellular lipid stores and lipolysis. Lipid droplet triglycerides and cholesterol are taken up by autophago-lysosomes for degradation, which finally generate free fatty acids to provide cellular energy through mitochondrial β-oxidation, also called lipophagy.^[36] As currently known, excessive lipid accumulation is regarded as the starting event of NAFLD. Thus, the autophagic function may exert potentially beneficial effects on NAFLD mainly by decreasing triglyceride and cholesterol accumulation.^[37] Amir and Czaja^[38] pointed out that autophagy could be considered as a therapeutic target in NASH by attenuating insulin resistance as well as by preventing cellular oxidation and hepatocellular carcinoma development.

 

Autophagy activation contributes to the beneficial metabolic effects of chronic exercise on NAFLD. He et al^[39] illustrated that the induction of autophagy by physical exercise exhibits beneficial metabolic effects, which may represent a cellular mechanism by which exercise prolongs life and protects hepatocytes against inflammatory diseases such as NASH. In addition, Kim et al^[40] demonstrated that treadmill exercise training enhances the age-triggered attenuation of autophagic proteins in mice, indicating that exercise training-induced autophagic response could be regarded as cellular "clearance" mechanism to protect hepatocytes against the accumulation of dysfunctional mitochondria and unfolded proteins. Similarly, 8 weeks treadmill exercise also induces autophagy in the cerebral cortex of adult mice, and it has been proven that exercise-induced autophagy in the brain mediates some neuroprotective effects.^[41] Even though the mechanism has not been shown, a reasonable speculation could be deduced that exercise is considered as a newly defined stimulus that triggers autophagy, leading to the attenuation of NAFLD pathology ultimately.

 

 

Since the molecular mechanisms of the beneficial effects of exercise on NAFLD have not been clarified, more studies are needed. First, ROS known to be associated with exercise are multifaceted signaling molecules implicated in a variety of cellular programs such as oxidative stress, apoptosis and autophagy.^[42] Thus, the functional or multi-functional role of ROS in exercise regulating NAFLD/NASH networks needs to be addressed. Second, autophagy is a fundamental mechanism to degrade lipid droplet-stored triglycerides and cholesterol via a process called lipophagy.^[43] Therefore, whether exercise could influence lipophagy in NAFLD/NASH should also be investigated. Third, inflammation is a hallmark of NASH. Autophagy has been shown as a critical signaling pathway to regulate the innate immune response by digesting pro-inflammatory mediators. As a result, how exercise influences autophagic proteins related to inflammation in NAFLD/NASH still needs investigation.^[44] Finally, there are several key factors involved in the crosstalk between apoptosis and autophagy. For example, caspase-9, an apoptotic marker, is directly involved in lysosome membrane related autophagic signaling pathways.^[45] Wirawan et al^[46] found that caspase-dependent cleavage of Beclin-1 blocks Beclin-1-triggered autophagy and increases apoptosis by enhancing the release of pro-apoptotic factors from mitochondria. Maiuri et al^[47] also illustrated that autophagy related gene ATG5 could induce apoptosis through several mechanisms which govern the crosslink between apoptosis and autophagy. Our unpublished data on NASH-induced by high fat diet and chronic exercise animal experiment showed that chronic exercise initially mitigated oxidative stress caused by NASH through the cytochrome P450 2E1 dependent pathway, further leading to the reduction of mitochondria-dependent hepatocyte apoptosis. Physical exercise also induced autophagy which diminished the extra lipid droplets via lipophagy and digested damage components generated from NASH process. It also ameliorated mitochondria-dependent hepatocyte apoptotic cell death by triggering mitophagy. As described above, exercise triggers autophagy and reduces hepatocyte apoptosis in NASH. Thus, future studies should elucidate which molecule(s)/signaling pathway(s) play essential role(s) in crosslinking between apoptosis and autophagy during physical exercise.

 

 

The mechanisms of exercise influencing the outcome of NAFLD may involve the following aspects which are summarized in Fig. During chronic training, the SREBP-1c and PPARγ mRNA and protein expression levels are down-regulated and up-regulated respectively in order to inhibit high fat diet induced NAFLD. For the positive effect on NAFLD-induced oxidative stress and inflammation, exercise acts as an ROS regulator to provide a stable condition for cell survival, and also significantly enhances the expression levels of antioxidant enzymes as well as anti-inflammatory mediators. In addition, physical exercise attenuates hepatocyte apoptosis triggered by fatty liver by regulating apoptotic pathways. Cytoprotective autophagy is activated during NAFLD progression to clean up the cellular dysfunctional substance and maintains energy balance. Nevertheless, the mechanism of the multi-factorial ameliorative effects of exercise on NAFLD has not been elucidated, hence additional investigations are required to examine the specific roles of exercise in the metabolic networks and the crosstalk among the main signaling pathways.

 

 

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