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Therapeutic Approaches to Nonalcoholic Fatty Liver Disease: Exercise Intervention and Related Mechanisms.

ABSTRACT: Exercise training ameliorates nonalcoholic fatty liver disease (NAFLD) as well as obesity and metabolic syndrome. Although it is difficult to eliminate the effects of body weight reduction and increased energy expenditure-some pleiotropic effects of exercise training-a number of studies involving either aerobic exercise training or resistance training programs showed ameliorations in NAFLD that are independent of the improvements in obesity and insulin resistance. In vivo studies have identified effects of exercise training on the liver, which may help to explain the "direct" or "independent" effect of exercise training on NAFLD. Exercise training increases peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1?) expression, improves mitochondrial function and leads to reduced hepatic steatosis, inflammation, fibrosis, and tumor genesis. Crosstalk between the liver and adipose tissue, skeletal muscle and the microbiome is also a possible mechanism for the effect of exercise training on NAFLD. Although numerous studies have reported benefits of exercise training on NAFLD, the optimal duration and intensity of exercise for the prevention or treatment of NAFLD have not been established. Maintaining adherence of patients with NAFLD to exercise training regimes is another issue to be resolved. The use of comprehensive analytical approaches to identify biomarkers such as hepatokines that specifically reflect the effect of exercise training on liver functions might help to monitor the effect of exercise on NAFLD, and thereby improve adherence of these patients to exercise training. Exercise training is a robust approach for alleviating the pathogenesis of NAFLD, although further clinical and experimental studies are required.

SUBMITTER: Takahashi H

PROVIDER: S-EPMC6196235 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Therapeutic Approaches to Nonalcoholic Fatty Liver Disease: Exercise Intervention and Related Mechanisms.

Takahashi Hirokazu H Kotani Kazuhiko K Tanaka Kenichi K Egucih Yuichiro Y Anzai Keizo K

Frontiers in endocrinology 20181015

Exercise training ameliorates nonalcoholic fatty liver disease (NAFLD) as well as obesity and metabolic syndrome. Although it is difficult to eliminate the effects of body weight reduction and increased energy expenditure-some pleiotropic effects of exercise training-a number of studies involving either aerobic exercise training or resistance training programs showed ameliorations in NAFLD that are independent of the improvements in obesity and insulin resistance. <i>In vivo</i> studies have ide ...[more]

PMID: 30374329

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Project description:BackgroundPhysical inactivity is a major risk factor for nonalcoholic fatty liver disease (NAFLD). Exercise-based prevention interventions for improving cardiorespiratory fitness are a recommended complementary treatment for NAFLD. Achievement of minimally effective physical activity to improve cardiorespiratory fitness among patients typically involves high personal and financial expenses in face-to-face settings. We designed an eHealth approach for patients with NAFLD to improve the cardiorespiratory fitness and report the first results of the HELP (Hepatic Inflammation and Physical Performance in Patients With NASH [nonalcoholic steatohepatitis]) study.ObjectiveWe aimed to assess the effectiveness of an 8-week, tailored, Web-based exercise intervention for cardiorespiratory fitness improvement, expressed as peak oxygen uptake (peak volume of oxygen [VO2peak]), in patients with histologically confirmed NAFLD.MethodsIn a 24-month period, 44 patients were enrolled into an 8-week, prospective, single-arm study with 12 weeks of follow-up. After a medical examination and performance diagnostics, a sports therapist introduced the patients to a Web-based platform for individualized training support. Regular individual patient feedback was provided to systematically adapt the weekly exercise schedule, which allowed us to monitor and ensure patient adherence to strength and endurance training and optimize the step-wise progressive exercise load. Exercise progression was based on an a priori algorithm that considered the subjective rate for both perceived exhaustion and general physical discomfort. The VO2peak was assessed at baseline and at the end of the study by spiroergometry.ResultsA total of 43 patients completed the intervention with no adverse events. The VO2peak increased significantly by 2.4 mL/kg/min (8.8%; 95% confidence interval [CI]: 1.48-3.27; P<.001) accompanied by a reduction of 1.0 kg in a body weight (95% CI: 0.33-1.58; P=.004) and 1.3 kg in body fat mass (95% CI: 0.27-2.27; P=.01). In an exploratory analysis, step-wise logistic regression analysis revealed low body fat and VO2peak at baseline and the total minutes of endurance training during the intervention as main contributors to a positive change in VO2peak. Our predictive model indicated that the average patient with NAFLD needed 223 min for stabilization of VO2peak and 628 min for average improvement in VO2peak. However, in patients with a VO2peak approximately 20% higher than the average VO2peak, 628 min were only sufficient to stabilize the VO2peak and >40% reduction in the average fat mass would be required to achieve an average outcome.ConclusionsThis is the first study to show that patients with NAFLD can be effectively supported by a Web-based approach, which can increase the VO2peak to a similar extent as face-to-face interventions. Patients with low body fat and low VO2peak benefited the most from our intervention. In terms of future treatment strategies, NAFLD patients with high body fat may particularly benefit from body-fat reduction through a strict nutritional intervention, subsequently enabling a more effective exercise intervention.Trial registrationClinicalTrials.gov NCT02526732; https://clinicaltrials.gov/ct2/show/NCT02526732 (Archived by WebCite at http://www.webcitation.org/74pXhXXfq).International registered report identifier (irrid)RR2-10.2196/resprot.8607.

Project description:Nonalcoholic fatty liver disease (NAFLD) is a rising global public health concern due to its prevalence. Danning Tablets (DNt), a composite prescription of Chinese herbal medicine, shows significant curative effects on NAFLD in clinical application. This study aimed to decipher the bioactive substances and potential mechanisms of action of DNt in the treatment of NAFLD, applying an integrated network pharmacology approach. First, the bioactive compounds of DNt were screened based on their pharmacokinetic properties, and the corresponding drug targets were predicted. Then, the NAFLD-related targets were collected. The overlapping targets between the putative targets of DNt and NAFLD-related targets were identified as the potential therapeutic targets of DNt against NAFLD. Subsequently, the networks were constructed and analyzed, and the key bioactive compounds and targets were screened out depending on their importance in the networks. Functional enrichment analysis was carried out to elucidate the potential mechanisms of DNt acting on NAFLD. Finally, a molecular docking simulation was implemented to assess the potential binding affinity between the key targets and the bioactive compounds. As a result, 43 bioactive compounds of DNt and 69 putative targets were identified. Based on the network analysis, we found seven key bioactive compounds (quercetin, ß-sitosterol, luteolin, kaempferol, supraene, curcumenolactone C, and stigmasterol) of DNt might treat NAFLD via intervening IL6, MAPK8, VEGFA, CASP3, ALB, APP, MYC, PPARG, and RELA. The functional enrichment analysis revealed that DNt might affect NAFLD by modulating the signaling pathways involved in lipid metabolism, inflammation, oxidation, insulin resistance (IR), atherosclerosis, and apoptosis. Furthermore, most key bioactive compounds might bind firmly with the key targets. This study predicted the multicomponent, multitarget, and multipathway mechanisms of DNt in the treatment of NAFLD from a holistic perspective. DNt could be a promising agent for NAFLD, but further experimental verifications are still needed.

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Therapeutic Approaches to Nonalcoholic Fatty Liver Disease: Exercise Intervention and Related Mechanisms.

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Therapeutic Approaches to Nonalcoholic Fatty Liver Disease: Exercise Intervention and Related Mechanisms.

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