Aerobic exercise in the management of metabolic dysfunction associated fatty liver disease

REVIEW Aerobic Exercise in the Management of Metabolic Dysfunction Associated Fatty Liver Disease Mariana Verdelho Machado 1,2 1 Serviço de Gastrenterologia, Hospital de Vila Franca de Xira, Vila Franca de Xira, Portugal; 2 Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal Abstract: Sedentarism is the pandemic of modern times. It is associated with several medical conditions including obesity, type 2 diabetes mellitus, cardiovascular diseases and also liver disease, particularly metabolic dysfunction associated fatty liver disease (MAFLD). In an era when MAFLD is the most prevalent chronic liver disease worldwide, whilst no pharmacological therapy has been approved for it, exercise has proved to be effective in improving liver steatosis. Interestingly, exercise decreases liver fat even in the absence of weight loss. The challenge for the clinician is to motivate the obese patient with MAFLD, and associated co-morbidities, who has crystallized a sedentary behavior, at times when every need is at the distance of a click on the Internet, and the entire world can be visited behind a screen. In this review, the aggregate evidence on the mechanisms and effects of exercise in the management of MAFLD is summarized, with simple recommendations for everyday clinical practice. Keywords: metabolic dysfunction-associated fatty liver disease, physical activity, aerobic exercise Introduction Sedentarism and unhealthy dieting are the pandemic behaviors of the XXI century. 1 Around 85% of the US population achieve less than what is preconized by the World Health Organization for daily physical activity for health. 2 Up to one third of the world’s population is physically inactive, which is strongly associated with obesity, type 2 diabetes mellitus, cardiovascular diseases and overall mortality. 3–5 Physical inactivity is also associated with metabolic dysfunction-associated fatty liver disease (MAFLD), independently of body weight. 6 MAFLD refers to the ectopic accumulation of fat in the hepatocytes, which can be explained by metabolic dysfunction associated with adiposopathy. Adiposopathy is the consequence of an energy overload in the adipose tissue, usually in overweight/obese patients. An overwhelmed adipose tissue can also arise in subjects with normal body mass index, in which the personal fat threshold, that is the amount of fat the individual adipose tissue can handle, is surpassed. 7 The sick adipose tissue releases fat that accumulates ectopically in the liver, but also in the cardiovascular system, and promotes systemic inflammation, insulin resistance, and the metabolic syndrome. The fatty liver further enhances insulin resistance and derangements in lipid metabolism, ensuing in a loop of metabolic dysfunction. 8 Recently, an international panel of experts proposed the following diagnostic criteria for MAFLD: 9 presence of hepatic steatosis in patients with type 2 diabetes Correspondence: Mariana Verdelho Machado Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, Lisboa, 1649-035, Portugal Tel +35 1912620306 Email mver[email protected] Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 3627–3645 3627 © 2021 Machado. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article Received: 25 May 2021 Accepted: 29 July 2021 Published: 11 August 2021 Diabetes, Metabolic Syndrome and Obesity downloaded from https://www.dovepress.com/ For personal use only. mellitus and/or who are overweight/obese. In lean nondiabetic patients, it requires evidence of hepatic steatosis and the presence of at least 2 of the following metabolic abnormalities: (1) Waist circumference (WC) ≥ 102 and 88 cm in Caucasian men and women, respectively (or ≥ 90 and 80 cm in Asian men and women, respectively); (2) Blood pressure ≥ 130/85 mmHg or specific drug treatment; (3) Plasma triglycerides ≥ 150 mg/dL or specific drug treatment; (4) Plasma high-density lipoprotein (HDL)- cholesterol < 40 mg/dL for men and < 50 mg/dL for women or specific drug treatment; (5) Prediabetes (ie, fasting glucose levels 100–125 mg/dL, or 2-h post-load glucose levels 140–199 mg/dL or HbA1c 5.7–6.4%); (6) Homeostasis model assessment (HOMA) of insulin resistance score ≥ 2.5; (7) Plasma high-sensitivity C-reactive protein level > 2 mg/L. MAFLD, 9 is the liver pandemic of our times. It afflicts up to one fourth of the global population. 10 It is also the most rapidly increasing etiology for end-stage liver disease, 11 being the second leading cause of chronic liver disease in patients on waitlist for liver transplantation overall, but already the leading cause in women. 12 Importantly, MAFLD is not only associated with an increased liver-related mortality but also associated with increased all-cause mortality. 13 Indeed, even though a recent meta-analysis could not demonstrate an association between MAFLD and cardiovascular mortality, 13 the presence of MAFLD increases over 60% the risk of having cardiovascular events, which cannot be solely explained by the association between MAFLD, obesity and the metabolic syndrome. 14 Up to now, there is no approved treatment for MAFLD, and the management of these patients relies on the promotion of a healthy lifestyle, with diet and exercise, aiming for weight loss. 15 The definition of sedentarism is not consensual and is often rendered as sitting time. Conversely, physical activity refers to any energy-requiring movement. Physical fitness is a set of attributes that reflect tolerance to physical activity and can be measured by specific tests. Exercise refers to planned physical activity that is structured and repetitive, with a specific intensity, frequency and duration. 16 The intensity of exercise can be graded according to the metabolic equivalent tasks (METs) spent. One MET refers to the amount of oxygen consumed while sitting at rest, and corresponds to 3.5 mL of oxygen per kg of body weight per minute. One MET is equivalent to 1 kcal per kg of body weight per hour. 17 For example, walking at a speed of 4.8 kms per hour is equivalent to 3 METs, while jogging at a speed of 6.4 to 8 kms per hour is equivalent to 7 METs. Exercise is considered light when it spends 1.1–3.9 METs; moderate 4–6 METs and vigorous/ intense to more than 6 METs. Another way to represent it is according to the VO 2 max, that is, the maximum capacity of oxygen utilization expressed as L/min. 18 Exercise is considered moderate when requires 40–60% of VO 2 , and vigorous when it requires at least 60%. There are 3 different types of exercise: aerobic, resistance and flexibility. Aerobic or endurance exercise is rhythmic, can be maintained continuously and relies on large muscle groups. Resistance or strengthening exercise exerts muscle overload requiring anaerobic metabolism. Lastly, flexibility or stretching exercise aims to increase the joint range of motion and muscle extensibility. 19 In this review, we will critically summarize the evidence of the effect of exercise on the management of MAFLD, with particular emphasis on aerobic exercise. What is the Role of Physical Activity in the Development and Progression of MAFLD? Epidemiological studies displayed an inverse correlation between physical activity and the prevalence of MAFLD, independently of the way physical activity was assessed: recalls, diaries, questionnaires or motion sensors/accelerometers, as shown in Table 1. In a cross-section Korean study with 3718 participants, physical activity evaluated through structured questionnaires showed an inverse association with the risk of having MAFLD, which was independent of visceral adipose tissue. Indeed, being on the highest quartile of physical activity decreased by almost one third the risk of having MAFLD 20 and to half the risk of developing de novo MAFLD. 21 A large cohort of 42,661 participants from the Netherlands showed similar associations. 22 Even lower levels of physical activity than the recommended (that is at least 150 minutes per week) conferred benefit over being entirely inactive. 22 Furthermore, patients with insulin resistance/type 2 diabetes mellitus and elderly benefited the most. 22 The association between physical activity, assessed by questionnaires, and MAFLD was corroborated by several studies in different populations: European, 23 Israeli, 24 Asian Indians, 25 Chinese, 26 and Korean. 27 The aggregate studies suggested a dose–response association. 26 Furthermore, the https://doi.org/10.2147/DMSO.S304357 DovePress Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 3628 Machado Dovepress Powered by TCPDF (www.tcpdf.org) Table 1 Observational Studies Evaluating the Effect of Physical Activity on MAFLD Reference Country Study Design N Evaluation of Physical Activity Diagnosis of MAFLD Main Results Perseghin G, 2007 23 Italy Crosssectional, Cohort 191 Questionnaire 1 H-MRS ● Inverse correlation between hepatic fat content and PA. ● ↓ prevalence of MAFLD according to quartile of PA: 25 > 11 < 25 >2% Zelber-Sagi S, 2008 24 Israel Crosssectional, Cohort 349 Self-reported PA in the last year Abdominal US ● The MAFLD group engaged in less aerobic or resistance PA Kistler KD, 2011 42 USA Crosssectional, Cohort 813 MAFLD patients Self-reported PA questionnaire from the NHANES Liver biopsy ● Moderate-intensity PA did not associate with steatohepatitis or fibrosis stage ● Vigorous PA ↓ risk of steatohepatitis: OR 0.65 [0.43–0.98] ● Doubling recommended time spent in vigorous PA ↓ risk of advanced fibrosis: OR 0.53 [0.29–0.97] Gerber L, 2012 32 USA Crosssectional, Cohort 3056 Activity counts from accelerometer readings for 7 days FLI >60 ● Patients with MAFLD spent less time participating in activity at any level ● Average PA was 28.7 counts/minute/day lower in MAFLD patients than controls Bae JC, 2012 37 Korea Crosssectional, Cohort 72359 Self-reported questionnaires Abdominal US ● Subjects who exercised >3x/week, ≥30 min/ session, for 3 consecutive months presented lower risk of MAFLD: OR 0.53–0.72 Miyake T, 2015 38 Japan Crosssectional, Cohort 6370 Questionnaire Abdominal US ● Periodical exercise ↓ risk of having MAFLD: OR 0.707 [0.546–0.914] Kwak MS, 2015 20 Korea Crosssectional, Cohort 3718 PA questionnaire from the NHANES Abdominal US ● PA was inversely associated with MAFLD: ● 4th vs 1st quartile: OR 0.68 [0.54–0.85] ● 3rd vs 1st quartile: OR 0.74 [0.59–0.93] Ryu S, 2015 6 Korea Crosssectional, Cohort 139056 International PA Questionnaire Short Form (Korean version) Abdominal US ● Prevalence of MAFLD ↓ in physically active vs inactive: ● Minimally active group: OR 0.94 [0.02–0.95] ● HEPA group: OR 0.8 [0.78–0.82] ● Prevalence of MAFLD ↑ with increasing sitting time: ● 5–9 hours/day: OR 1.04 [1.02–1.07] ● ≥ 10 hours/day: OR 1.09 [1.06–1.11] Hallsworth K, 2015 33 UK Crosssectional, Casecontrol 37 MAFLD, 37 controls Sedentary behaviour, PA and E expenditure were assessed by a multisensor array over 7 days 1 H-MRS ● MAFLD patients compared to controls: ● Spent an hour extra per day being sedentary ● Walked 18% fewer steps ● ↓ active E expenditure by 40% ● ↓ total E expenditure by 8% Tsunoda K, 2016 43 Japan Prospective cohort, FU 4.2 years 1149 Questionnaire MAFLD: by US; steatohepatitis by ↑ ALT or AST ● Vigorous PA prevented progression to steatohepatitis: OR 0.55 [0.32–0.94] ● Moderate or low intensity PA presented no association with progression to steatohepatitis (Continued) Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 https://doi.org/10.2147/DMSO.S304357 DovePress 3629 Dovepress Machado Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) Table 1 (Continued). Reference Country Study Design N Evaluation of Physical Activity Diagnosis of MAFLD Main Results Sung KC, 2016 40 Korea Prospective cohort, FU 4.95 years 169347 International PA Questionnaire Short Form (Korean version) Abdominal US ● ≥5x/week exercise vs no exercise: ● ↓ risk of incident steatosis: OR 0.86 [0.80–0.92] ● ↑ likelihood of steatosis resolution: OR 1.40 [1.25–1.55] Wei H, 2016 28 China Crosssectional, Cohort 2054 male Self-reported questionnaire FLI ≥60 ● Dose-dependent ↑ prevalence of MAFLD across the tertiles of sitting time. ● Sitting time >7.1 hours/day associated with ↑ prevalence of MAFLD (OR 1.09 [1.04–1.67]) Keating SE, 2016 34 Australia Crosssectional, Cohort 82 Activity counts from accelerometer readings for 4 days 1 H-MRS ● No associations between PA and sedentary behavior and the prevalence of MAFLD Kwak MS, 2017 21 Korea Prospective cohort, FU 4.2 years 1373 PA questionnaire from the NHANES Incident MAFLD by US ● Total and leisure PA was inversely associated with incident MAFLD ● ↓ PA at FU associated with ↑ incident MAFLD: 4th quartile vs 1st quartile of ↓ PA OR 1.45 [1.04–2.02] Byambasukh O, 2019 22 Netherlands Crosssectional, Cohort 42661 Self reported questionnaire to evaluate HEPA FLI ≥60 ● Higher moderate/vigorous PA was dosedependently associated with ↓ risk of MAFLD: OR for PA quintiles: 0.78 [0.71–0.86] > 0.64 [0.58–0.70] > 0.53 [0.48–0.59] > 0.51 [0.46–0.56] ● Even PA lower than recommendations was better than inactivity ● Occupational PA offers no clear health benefits Li YF, 2019 26 China Crosssectional, Casecontrol 543 MAFLD, 543 controls International PA Questionnaire Short Form (Chinese version) Abdominal US ● Both moderate (OR 0.62 [0.41–0.92]) or vigorous (OR 0.60 [0.40–0.91]) intensity PA associated with ↓ risk of MAFLD in men, independently of sedentary time or E expenditure Jang DK, 2019 27 Korea Crosssectional, Casecontrol 32391 Self reported questionnaire to evaluate HEPA Hepatic steatosis index ● PA negatively associated with MAFLD (most vs least active: OR 0.7 [0.6–0.8]) and lean MAFLD (OR 0.5 [0.4–0.7]) Gerage AM, 2019 41 Brazil Prospective cohort, FU 2.5 years 5860 International PA Questionnaire Abdominal US ● Lower likelihood of improving steatosis in subjects who remained inactive (OR 0.64) or became inactive (OR 0.66) ● Lower risk of acquiring MAFLD in subjects who remained active (OR 0.75) or became active (OR 0.75) Bhatt SP, 2019 25 India Crosssectional, Casecontrol 342 Questionnaire Abdominal US ● Mean PA was lower in cases than controls (33.3 ±3.6 vs 36.2±0.5 MET/min) ● Total E expenditure was lower in cases than controls (2707.6±505.6 vs 2904.3±690.3 kcal) Croci I, 2019 29 Australia Crosssectional, Cohort 15781 Self-reported questionnaire FLI ≥60 ● For each additional 1 hour/day of sedentary behavior, the risk of having MAFLD ↑ 4% [3–6] ● High cardiorespiratory fitness attenuated the negative role of sedentary behavior up to 7 hours/ day on MAFLD. (Continued) https://doi.org/10.2147/DMSO.S304357 DovePress Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 3630 Machado Dovepress Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) protective effect of physical activity was equally strong in patients with lean MAFLD. 27 A cross-sectional study on 139,056 Korean, who underwent a comprehensive annual or biennial health examination, showed that spending more than 5 hours sitting per day increased the risk of having ultrasonography-diagnosed MAFLD. 6 Other studies in Asian and Australian populations confirmed a dose–response association between sitting time and the prevalence of MAFLD. 28–30 Indeed, spending more than 7 hours sitting per day increased by 10% the risk of MAFLD, independently of body mass index (BMI), insulin resistance and dyslipidemia. 28 The detrimental effect of spending more than 10 hours sitting per day persisted even in those who were otherwise physically active. 6 These results point out to the difference between inactivity and absence of exercise. Indeed, a small study on 19 overweight or obese adults showed that decreasing sitting time through 2 minutes bouts of light to moderate intensity walking was effective in decreasing insulin resistance. 31 Other studies used a more objective way to quantify physical activity, such as accelerometers. Indeed, a study with 3056 participants from the National Health and Nutrition Examination Survey (NHANES) evaluated the physical activity during 7 consecutive days through accelerometer readings. When the accelerometer recorded less than 100 counts per minute per day, the patient was considered sedentary. MAFLD was diagnosed when fatty liver index (FLI) was higher than 60 and in the absence of other chronic liver diseases. In this study, patients with MAFLD spent less time participating in any activity, and presented an average of around less than 30 counts/min/day as compared to controls. 32 Similarly, a small study from Newcastle, UK, evaluated 7-days physical activity and energy expenditure using a multisensory array on 37 patients with MAFLD and 1000 healthy controls. MAFLD patients spent an extra hour being sedentary, walked up to one-fifth fewer steps and expended 40% less energy being active. 33 A small study from Australia failed to corroborate this association, 34 when hepatic steatosis was measured by magnetic resonance spectrometry (MRS). Importantly, not all physical activities seem to equally promote health. Indeed, it is leisure or recreational, and not occupational, physical activity that seems to induce the most benefits in health. Recreational physical activity usually induces the contraction of large muscle groups while increasing whole-body metabolism and cardiac output. During recreational physical activity one can rest when fatigued. Occupational physical activity more frequently involves heavy lifting, prolonged standing, and highly repetitive movements. 35 Epidemiologic studies suggest an inverse, dose–response association between the risk of hypertension and recreational, but not occupational, physical activity. 35 Furthermore, recreational physical activity is associated negatively, whereas occupational positively, with BMI, central obesity and insulin resistance. 36 Similarly, large-population studies have shown that recreational, but not occupational, physical activity seems to be protective against having MAFLD. 22 Regarding the practice of exercise, a large population Korean study also showed that subjects that practiced exercise at least 3 times per week, for at least 30 minutes each time for more than 3 months, decreased up to half the risk of having MAFLD. 37 A cross-sectional study from a subsample of 375 participants in the Israeli National Health And Nutrition Survey showed that engaging in any kind of sports decreased one-third the risk of having Table 1 (Continued). Reference Country Study Design N Evaluation of Physical Activity Diagnosis of MAFLD Main Results Joo JH, 2020 30 Korea Crosssectional, Cohort 13518 International PA Questionnaire (Korean version) Hepatic steatosis index ● The offs of having MAFLD increased across quartiles of sitting hours: 1.07 [0.88–1.31] < 1.16 [1.06–1.41] < 1.34 [1.11–1.61] Kim D, 2021 52 USA Prospective cohort, FU 10.6 years 5207 MAFLD patients PA questionnaire Abdominal US ● ↑ duration of PA inversely associated with allcause mortality (higher vs lower quartile: OR 0.46 [0.28–0.75]) and cardiovascular mortality (OR 0.28 [0.008–0.98]) in patients with MAFLD Abbreviations: E, energy; FLI, Fatty Liver Index; HEPA, health-enhancing physically active; NHANES, National Health and Nutrition Examination Survey; PA, physical activity; US, ultrasound. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 https://doi.org/10.2147/DMSO.S304357 DovePress 3631 Dovepress Machado Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) MAFLD, per each standard deviation increase in the physical activity score. These associations were stronger for resistance exercise as compared to aerobic exercise, which was explained by probable misclassification of selfreported physical activity. 24 Similar results were shown on a large Japanese cohort. 38 Furthermore, engagement in regular exercise also seems to be associated with protection from incident MAFLD, improvement and remission of MAFLD. 39–41 Those effects presented a dose– response pattern and occurred for any amount of exercise. 40 Engaging in physical activity not only seems to confer protection from having MAFLD, but it is also associated with less severe disease, in a dose-dependent manner. Two large-population studies from the US and Japan showed that engaging in vigorous, but not moderate, physical activity decreased the chances of progression to steatohepatitis and liver fibrosis. 42,43 The authors hypothesized that vigorous physical activity consumes large amounts of ATP, which activates AMP kinase, eliciting increased ATP production through fatty acids oxidation and glucose transport. 44 Furthermore, vigorous physical activity can lead to depletion of hepatic glycogen, triggering fat consumption. 43 Another way to evaluate the role of physical activity on the development of MAFLD is through physical fitness, translating the ability of the subject to engage physical activity. Physically fit subjects, assessed using maximal treadmill exercise test or cycle ergometer data, seem less susceptible to having MAFLD, steatohepatitis, and severe liver fibrosis, independently of BMI. 45–50 A recent study followed 125,264 participants from the Nurses' Health Study and the Health Professionals Follow up Study, for up to 25 years. It showed that higher physical activity also predicted a lower risk of liver-related mortality, across all the range of BMI. Physical activity could even abrogate the excessive liver-related mortality observed with obesity. Indeed, walking at least 3 hours per week could have prevented 25% of liver-related deaths. 51 Furthermore, engaging in physical activity seems to have a profound impact on the survival of patients with MAFLD. A study that evaluated 5207 participants from the NHANES followed them for 10 years, assessing physical activity by accelerometer readings. The duration spent on physical activity was inversely associated with all-cause mortality. Subjects with the highest quartile of physical activity presented a more than half decreased risk of all-cause mortality compared to the lowest quartile of physical activity. The effect was even stronger for cardiovascular mortality. 52 A different Australian cohort that also followed MAFLD patients over a 10-year period and showed that low cardiorespiratory fitness was associated with a 50% increase in allcause mortality. 29 Physiopathology of Exercise and MAFLD MAFLD occurs when there is an imbalance between fat uptake and triglycerides production in the liver, and hepatic fat oxidation. Most of the fat uptake into the liver derives from the adipose tissue, particularly visceral adipose tissue. Insulin resistance promotes the release of fat from the adipose tissue that can reach the liver, and also, increases hepatic lipogenesis. In the liver, lipotoxicity can induce cell stress, through different mechanisms, such as oxidative stress, ER stress, impaired autophagy and cell death. 8 Metabolic systemic inflammation and gut dysbiota also seem to play a role in the development and progression of MAFLD. 53 Physical activity and exercise can protect against MAFLD through several mechanisms, acting on different players, such as the adipose tissue, the muscle, directly on the liver and on the gut microbiota 54 (Figure 1). Exercise can decrease visceral adiposity, particularly aerobic exercise. 55 The decrease in visceral adipose tissue decreases the influx of free fatty acids into the liver. 56 It also decreases the metabolic-associated systemic inflammation while improving the adipokine profile (inducing an increase in adiponectin and a decrease in leptin). 57,58 Exercise not only decreases the quantity of the adipose tissue but also changes the structure and function of the adipocyte. The importance of the qualitative changes in the adipose tissue induced by exercise can be illustrated by an interesting experiment in which recipient sedentary mice were transplanted with adipose tissue from trained donor mice (voluntary wheel running for 11 days). The recipient mice experienced a dramatic improvement in glucose tolerance. 59 Exercise decreases adiposity by decreasing the size of the adipocytes and its lipid content. 60 This is of extreme relevance since the enlargement of adipocytes induces cellular stress (for example, oxidative and ER stress), 61,62 leading to a distinct adipokine profile, to insulin resistance 63 (which increases its lipolytic capacity by spilling out of free fatty acids into the circulation), 64 and to https://doi.org/10.2147/DMSO.S304357 DovePress Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 3632 Machado Dovepress Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) cell death 65 promoting adipose tissue inflammation. 66 Furthermore, exercise induces beijing of the white adipose tissue, conferring a brown-like phenotype, with increased mitochondrial activity, 59 increased uncoupling proteins leading to increased thermogenesis and increased energy expenditure. 67,68 Exercise also protects against MAFLD through its effects on the muscle. Regular exercise increases the muscle capacity for oxygen consumption and oxidative function, by increasing capillary density and increasing muscle mitochondrial content and function, 69 for example through upregulation of proteins involved in mitochondrial biogenesis, such as peroxisome proliferator-activated receptor gamma (PPAR-γ) co-activator 1-alpha (PGC1α). 18 The muscle is the main tissue for glucose uptake and storage. 70 Exercise and muscle contraction promote muscle glucose uptake by the translocation of the glucose receptor GLUT-4 into the cellular membrane, independently of insulin action, and by increasing muscle insulin sensitivity. 71,72 Also, exercise increases the muscle glucose storage as glycogen. 73,74 On the other hand, during exercise, the redistribution of blood flow from the splanchnic circulation to the working muscles, redirects circulating free fatty acids from the liver into the muscle. 75 Indeed, regular exercise increases the uptake and oxidation of fatty acids by the muscle, as well as the ability to store fatty acids such as intramyocellular triglycerides. 76 The relative contribution of glucose as fuel, compared to fat, increases with work rate, but declines with exercise duration. 77 Furthermore, in the post-exercise period, glucose oxidation decreases at the expense of fat oxidation, in order to replenish glycogen storage. 78 Lastly, exercise modulates myokines production. 7 Exercise induces the release of irisin that promotes beijing of white adipose tissue, increasing energy expenditure. 68 Irisin also has direct anti-steatogenic effects on the liver, through activation of PPAR-γ and upregulation of fibroblast growth factor (FGF)-21. 79 On the other hand, exercise downregulates myostatin, 80 a myokine that promotes adipose tissue expansion through direct effects on the adipose tissue and through downregulation of irisin. 81,82 Myostatin can also promote hepatic fibrogenesis through direct action on hepatic stellate cells. 83 Moreover, exercise increases transiently the synthesis of interleukin(IL)-6, 84 Figure 1 The anti-steatogenic mechanisms of exercise. Abbreviations: VAT, visceral adipose tissue; WAT, white adipose tissue; NEFA’s, non-esterified fatty acids; ER, endoplasmic reticulum. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 https://doi.org/10.2147/DMSO.S304357 DovePress 3633 Dovepress Machado Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) which induces subsequent increase in IL-10, IL-1 receptor antagonist and cortisol, with a net anti-inflammatory effect. 85 Exercise has independent anti-steatogenic effects on the liver. Studies on animal models showed that exercise decreases de novo lipogenesis by downregulating the lipogenic transcription factor sterol regulatory-element binding protein-1c (SREBP-1c) 86,87 and decreasing the levels and activity of key enzymes in lipid synthesis such as acetyl CoA carboxylase (ACC) and fatty acids synthase (FAS). 88 Simultaneously, exercise increases hepatic mitochondrial fatty acids oxidation, by upregulating the lipolytic transcription factor PPAR-γ 89 and increasing the activity of key enzymes in beta-oxidation such as betahydroxyacyl-CoA-dehydrogenase (β-HAD), citrate synthase and cytochrome c oxidase. 90–92 Exercise has an anti-oxidant effect on the liver, which translates into a decrease in lipid peroxidation, an increase in reduced glutathione content, and an increase in the activity of anti-oxidant enzymes, such as catalase, superoxide dismutase and glutathione peroxidase. 93–98 It also has an anti-inflammatory effect, through a decrease in systemic inflammation mediated by the adipose tissue 99 and the muscle, 85 and through direct effects on the liver. Exercise decreases the hepatic tumor necrosis factor-alpha (TNF-α) and hepatic resident macrophages infiltration. 100,101 Furthermore, it inhibits the expression of toll-like receptors (TLR) on monocytes and macrophages, 102 and increases the pool of T regulatory cells. 103 Physical activity/exercise modulates other important cellular pathways: it promotes hepatoprotective autophagy, 104 and it improves mitochondrial function, protecting the mitochondria from structural damage. 105–107 Moreover, exercise attenuates mitochondrial-dependent hepatocyte apoptosis. 108–110 All those actions are hepatoprotective, with the potential to decrease the progression from isolated steatosis to steatohepatitis and hepatic fibrosis. Animal studies also suggested exercise to decrease the risk of hepatocellular carcinoma in steatotic livers. 111–113 Finally, exercise can modulate the gut microbiota towards a less steatogenic and insulin sensitizer phenotype. Indeed, in humans, exercise is associated with an increase in microbial richness/diversity, 114,115 an increase in the relative proportion of Bacteroidetes and Euryarchaeota, whereas a decrease in Actinobacteria, at the phylum level. 116,117 Obesity and MAFLD are known to be associated with a decrease in the Bacteroidetes/ Firmicutes ratio, which is associated with higher efficiency in harvesting energy from the diet. 53 Furthermore, exercise helps preserve the intestinal barrier, and improves bile acids homeostasis. 118 Aerobic Exercise and MAFLD Several studies, mostly randomized controlled studies, and 7 meta-analyses evaluated the effect of structured interventions on aerobic exercise in MAFLD 119–125 as shown in Table 2. Studies used different exercise regimens, with different intensities, and with durations ranging 121 from 1 week 109 to 1 year. 126 Most of them showed improvements in hepatic steatosis. 54,127,128 A small percentage of published studies with negative results more often used less discriminative tools to quantify liver fat, such as CT scan. 129 The effect on liver fat of exercise-only interventions ranged from a decrease of 2% up to 50%. 121 Exercise also had a modest effect, decreasing aminotransferases levels. 120 Globally, the published studies found a significant positive correlation between changes in BMI and changes in liver fat content. 54,130 For each 1% decrease in body weight, studies reported 1% decrease in liver fat content. 123 The effect was also more profound when baseline BMI was higher. 120 However, improvements in liver steatosis were also reported in the absence of weight loss, 56,131–133 suggesting that exercise exerts beneficial effects on liver steatosis that are independent of weight loss. 54 This may be, in part, explained by a more consistent improvement in visceral/abdominal fat with preservation of muscle mass, 56,127,130,132,134–137 in insulin resistance and lipid profile, 135,136,138–140 and modification of inter-organ cross-talk with a favorable cytokine expression (for example, adiponectin and myostatin) and reduction of inflammation and oxidative stress, 141 after an exercise intervention. A predictor of the efficacy of an exercise intervention in reducing liver fat was baseline cardiorespiratory fitness, independently of total and visceral adipose tissue loss or exercise intensity. 142 Cardiorespiratory fitness probably reflected the functional consequences of genetics and recent physical activity habits. The beneficial effects of exercise on liver fat were transversal across the lifespan, with positive results from studies on adolescents 143 to the elderly. 144 However, the effect seemed to be more pronounced in the elderly. Exercise was also beneficial in patients with MAFLD who had normal weight at baseline. 7 https://doi.org/10.2147/DMSO.S304357 DovePress Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 3634 Machado Dovepress Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) Table 2 Randomized Controlled Studies Evaluating the Effect of Aerobic Exercise on MAFLD Reference Country N Intervention Controls Main Findings Intensity Sessions/ Week Duration Sullivan S, 2012 131 USA 19 obese MAFLD patients 45–55 VO 2 peak, 30–60 minutes 5 16 No exercise ● Exercise ↓ IHLC (10.3±4.6%) ● Exercise had no effect on weight or % of body fat Hallsworth K, 2015 33 UK 23 MAFLD patients H-I interval training 3 12 weeks Standard of care ● Exercise associated with: ● ↓ liver fat and whole body fat mass ● ↓ ALT and AST ● ↑ early diastolic filling rate ● No effect on glucose or lipid metabolism Keating SE, 2015 58 Australia 48 inactive overweight/ obese adults 1. L/M-I (50% VO 2 peak), 60 min, 4x/week 2. H-I (70% VO 2 peak), 45 min, 3x/week 3. L/M-I (50% VO 2 peak), 45 min, 3x/week 8 weeks No exercise ● L/M-I, 60 min, 4x/week: ↓ IHLC 2.62 ±1.00%, ↓ VAT 386.8±119.5 cm 2 ● H-I, 45 min, 3x/week: ↓ IHLC 2.38 ±0.73%, ↓ VAT 258.4±87.2 cm 2 ● L/M-I, 45 min, 3x/week: ↓ IHLC 0.84 ±0.45%, ↓ VAT 212.9±105.5 cm 2 ● Placebo: ↑ IHLC 1.10±0.62%, ↑ VAT 92.6±83.5 cm 2 Zhang HS, 2016 126 China 220 MAFLD patients with central obesity 1. H-I: 65–80% maximal HR 2. M-I: 45–55% maximal HR 150 minutes 6 months No exercise ● No difference on IHLC in M-I vs H-I exercise, even though H-I exercise associated with higher decrease in body weight ● No effect on aminotransferases ShojaeeMoradie F, 2016 127 UK 27 sedentary MAFLD patients 1 hour at 40– 60% HR reserve 4–5 16 weeks Conventional life-style advice ● Exercise versus control ↓ IHLC, visceral fat and subcutaneous abdominal fat and ↑ VLDL clearance Cuthbertson DS, 2016 140 UK 69 MAFLD patients 30% HR reserve 30 minutes → 60% HR reserve 45 minutes 3 → 5 16 weeks Counseling ● Greater ↓ of IHLC in intervention group (4.7% [0.01–9.4]), improvement on insulin sensitivity and SC abdominal fat Rezende R, 2016 132 Brazil 40 sedentary postmenopausal women Treadmill aerobic exercise 120 minutes 24 weeks No exercise ● Exercise associated with ↓ waist circumference ● Exercise did not associate with improvements on steatosis (by CAPFibroscan) or glucose metabolism Cheng S, 2017 139 China 115 patients with MAFLD and IR, 50–65 years 60–75% VO 2 max, 30–60 minutes ± fiberenriched diet 2–3 8.6 months No intervention ● Effect on IHLC: ● exercise alone: ↓ 24.4% ● diet alone: ↓ 23.2% ● exercise + diet: ↓ 47.9% ● no intervention: ↓ 20.9% ● Only exercise associated with ↓ HbA1c (Continued) Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 https://doi.org/10.2147/DMSO.S304357 DovePress 3635 Dovepress Machado Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) 73. 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