Aylar Birar

, Roghayyeh Afroundeh

, Mehdi Namaki

, Fereshteh Taherkhani

, Alireza Shafeei

, Abbas Hosseini

University of Mohaghegh Ardabili , afroundeh@gmail.com

Abstract: (260 Views)

Introduction Upwards of 30% of the world’s population has nonalcoholic fatty liver disease (NAFLD). At this point in time, there is no regulatory-agency-approved effective drug therapy or cure, and lifestyle modification with dietary change and increased physical activity remains crucial in the clinical management of all types of NAFLD, including nonalcoholic steatohepatitis (NASH), the more severe type. However, most patients with NAFLD do not meet recommended amounts of weekly physical activity, and no one optimal diet has been established, although a Mediterranean-informed diet appears to hold the most promise and is recommended by several leading gastroenterology and hepatology societies. despite decades of research in this field, how physical activity and exercise training lead to these benefits remains an area of much interest and ongoing scientific investigation. This interest parallels the ongoing work in drug development, where several pharmacologic agents have progressed to late-phase clinical trials and include drugs with diverse mechanistic targets, including those which impact the Farnesoid X receptor (FXR) signaling, glucagon-like peptide (GLP)-1, fibroblast growth factor (FGF)-19 and -21, thyroid receptor beta, peroxisome proliferator-activated receptor (PPAR) and adenosine monophosphate-activated protein kinase (AMPK) pathways. accordingly, the aim of this narrative review is to synthesize the current literature on the role of exercise training in these mechanistic pathways to underscore and highlight the utility of exercise as a principal management strategy for NAFLD.

Exercise Training and Mechanistic Pathways Involved in Hepatic Steatosis
1. AMPK is a fuel-sensing enzyme that is activated by energy stress and is composed of a trimeric complex with a catalytic subunit (α) and two regulatory subunits (β and γ). AMPK plays an important role in global energy balance. Importantly, exercise-induced AMPK activation appears to be dose-related. There is a clear and consistent body of evidence to support the role of the AMPK pathway as a key pathway modulated by exercise training that appears to be related to both intensity and exercise volume across animal and human studies.
2. FGF is a complex family of peptide hormones that has a crucial implication on regulating energy homeostasis and metabolism. Multiple isoforms of FGF are involved in the cascade, but FGF-19 and FGF-21 are closely related to fat metabolism and are the signaling pathways for both hormones involved in NAFLD and NASH development and the focus of drug discovery. Although closely related to FGF-21, exercise may play a different role in FGF-19 expression. To date, the scientific literature suggests that exercise training across different exercise intensities and volumes can activate FGF-21. No conclusions can be made about the relationship between FGF-19 and exercise training.
3. The liver plays a central role in insulin metabolism and is impacted by multiple gut hormones. One such hormone is GLP-1, an incretin, which helps to regulate satiety and lipid metabolism in both the fasting and glucose-stimulated states. Exercise can impact serum levels of GLP-1, and in fact, exercise can increase GLP-1 levels in healthy individuals and in persons with obesity and suppress appetite. While GLP-1 and other gut hormones present intriguing avenues of research, the existing scientific data prevent strong conclusions regarding the impact of exercise training programs on this therapeutic target.
4. Mitochondrial Function and Beta Oxidation: The liver plays a principal role in lipid metabolism as the primary site of de novo lipogenesis and fatty acid oxidation. In fact, lipid-derived energy production in the liver occurs through the β-oxidation of fatty acids. Regular exercise has been shown to improve mitochondrial oxidative capacity and increase mitochondrial content, which are related to increases in cardiorespiratory fitness. In fact, cardiorespiratory fitness is inversely related to hepatic steatosis, and improvements in cardiorespiratory fitness are independently associated with improvements in steatosis. As cardiorespiratory fitness has been shown to improve to a similar degree with both high-intensity interval training (HIIT) and more traditional moderate-intensity continuous training, this may, in part, explain why HIIT leads to similar improvements in hepatic steatosis to more moderate-intensity continuous exercise despite expending less energy. Although most work in this space has been conducted in animal models, the available data from human studies support the role of improving cardiorespiratory fitness as a key therapeutic target in the management of NAFLD.
5. Mitochondrial Uncoupling Proteins (UCP): Mitochondria are vital organelles that are at the forefront of cellular metabolism, especially in the liver, which is the primary metabolic organ in the human body. UCPs are a key component of mitochondrial metabolism and are mitochondrial inner-membrane proteins which mediate proton leak across the inner membrane through anion transport and uncouple substrate oxidation from ATP synthesis. In summary, animal models suggest a role for exercise training in upregulating UCPs; however, this remains unexplored in patients with NAFLD and NASH and we await confirmatory data in human subjects to further explore this as a mechanism by which exercise may ameliorate hepatic steatosis.
6. Peroxisome Proliferator-Activated Receptor (PPAR)-α/γ: PPARα is a nuclear receptor that plays a key role in regulating lipid metabolism. It is specifically activated by fatty acids and their derivatives. When expressed in the liver, PPARα is responsible for fatty acid catabolism and energy homeostasis. The PPARα pathway is known to be strongly influenced by exercise training in non-NAFLD populations, including patients who are physically inactive and are overweight or obese. To date, we are unaware of any studies in human subjects with NAFLD which have explored the impact of exercise training on the PPAR pathway to confirm the animal model findings summarized above. In summary, the current available evidence indicates that exercise-mediated activation of PPAR appears to be mediated by exercise intensity and volume, although the relative contribution of each remains unknown.
Conclusion

As rates of NAFLD and NASH increase worldwide in parallel with the obesity pandemic, there are key unmet needs to better understand this complicated disease. Despite years of scientific effort, a regulatory-agency-approved treatment for NAFLD and NASH is not yet available, although there are several promising medications on the horizon. Even when these medications are approved, regular physical activity, which is most effectively accomplished through a formal and supported exercise training program, will continue to be a vital component in not only the clinical management of NAFLD but also in its prevention. Moreover, emerging evidence suggests that exercise training at levels promoted in population physical activity guidelines is just as efficacious in MRI-measured liver fat reduction as anti-steatogenic medications which are both prescribed off-label and under development [8]. The question of the synergistic effect of exercise training with various drugs under development remains unknown. It is plausible that exercise training impacts nearly every therapeutic target of interest in NASH drug discovery. We look to future research to not only better define the mechanisms underlying the benefit of regular physical activity and exercise training in patients with NAFLD and NASH but also to further our exploration of the epigenetic-related impact of exercise training and precision-medicine based therapeutic response. With this future understanding, we can not only impact the one out of three adults with NAFLD worldwide but also the billions of individuals living with other chronic metabolic diseases.

Keywords: non-alcoholic fatty liver, steatosis, sports activity, molecular pathways

Type of Study: review article | Subject: Exercise Physiology

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