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Review
. 2018 May 18;18(2):89-101.
doi: 10.3727/105221617X15124844266408. Epub 2017 Dec 6.

The Effects of Physical Exercise on Fatty Liver Disease

Dirk J van der Windt  1 , Vikas Sud  1 , Hongji Zhang  1 , Allan Tsung  1 , Hai Huang  1
Affiliations
Review

The Effects of Physical Exercise on Fatty Liver Disease

Dirk J van der Windt et al. Gene Expr. .

Abstract

The increasing prevalence of obesity has made nonalcoholic fatty liver disease (NAFLD) the most common chronic liver disease. As a consequence, NAFLD and especially its inflammatory form nonalcoholic steatohepatitis (NASH) are the fastest increasing etiology of end-stage liver disease and hepatocellular carcinoma. Physical inactivity is related to the severity of fatty liver disease irrespective of body weight, supporting the hypothesis that increasing physical activity through exercise can improve fatty liver disease. This review summarizes the evidence for the effects of physical exercise on NAFLD and NASH. Several clinical trials have shown that both aerobic and resistance exercise reduce the hepatic fat content. From clinical and basic scientific studies, it is evident that exercise affects fatty liver disease through various pathways. Improved peripheral insulin resistance reduces the excess delivery of free fatty acids and glucose for free fatty acid synthesis to the liver. In the liver, exercise increases fatty acid oxidation, decreases fatty acid synthesis, and prevents mitochondrial and hepatocellular damage through a reduction of the release of damage-associated molecular patterns. In conclusion, physical exercise is a proven therapeutic strategy to improve fatty liver disease.

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Figures

Figure 1
Figure 1
Schematic overview of metabolic and molecular pathways involved in the pathobiology of nonalcoholic steatohepatitis (NASH) and the effects of physical exercise thereon. Peripheral insulin resistance causes an increase in delivery of glucose and FFA to the liver. FA synthesis further increases FFA levels. When the mechanisms for FA storage as triglycerides (steatosis) and metabolism (β-oxidation) become overwhelmed, ROS production increases, resulting in mitochondrial and hepatocyte damage, DAMP release, and amplification of inflammation. Exercise affects these pathways at multiple levels, as indicated. Of note, multiple other pathways are involved in the pathogenesis of NASH. As the effects of exercise have not been investigated on these pathways, they are not included in this diagram. AMPK, AMP-activated protein kinase; DAMP, damage-associated molecular pattern; FA, fatty acid; FFA, free fatty acids; HCC, hepatocellular carcinoma; HMGB1, high-mobility group box-1; HSC, hepatic stellate cell; IR, insulin resistance; MMIF, macrophage migration inhibitory factor; mtDNA, mitochondrial DNA; mTOR, mammalian target of rapamycin; PPARα, peroxisome proliferator-activated receptor-α; ROS, reactive oxygen species; SREBP-1, sterol regulatory element-binding protein 1.
Figure 2
Figure 2
Effects of physical exercise on hepatic fatty acid synthesis. In NASH, the increase in glucose delivery to the liver results in increased FFA synthesis. Exercise reduces the expression of various enzymes that mediate the conversion of acetyl-coA to FFA. An increase in AMPK by exercise stimulates the phosphorylation and therefore inactivation of these enzymes (here depicted for ACC) and of SREBP-1, which is a main transcription factor for expression of ACC, FAS, elongase, and SCD1. ACC, acetyl coenzyme A carboxylase; AMPK; FAS, fatty acid synthase; FFA; SCD1, stearoyl coenzyme A desaturase 1; SREBP-1. P denotes phosphorylation.
Figure 3
Figure 3
Effects of NASH and exercise on mitochondrial function. When β-oxidation fails to appropriately neutralize the access in FFA, ROS formation leads to lipid peroxidation products, which in return cause more mitochondrial damage. Physical exercise stimulates PPARα, which has beneficial effects on multiple aspects of β-oxidation and therefore improves mitochondrial quality and function. ACD, acyl coenzyme A dehydrogenase; CPT1/2, carnitine palmitoyl coenzyme A transferase 1/2; FFA; MDA, malondialdehyde; PPARα; TFE, trifunctional enzyme.
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