Exercise training reverses endothelial dysfunction in nonalcoholic fatty liver disease

Abstract

fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). Endothelial dysfunction is an early manifestation of atherosclerosis and an important prognostic marker for future cardiovascular events. The aim of this study was twofold: to examine 1) the association between liver fat, visceral adipose tissue (VAT), and endothelial dysfunction in obese NAFLD patients and 2) the impact of supervised exercise training on this vascular defect. Brachial artery endothelial function was assessed by flow-mediated dilatation (FMD) in 34 obese NAFLD patients and 20 obese controls of similar age and cardiorespiratory fitness [peak oxygen uptake (V O2 peak)] (48 Ϯ 2 vs. 47 Ϯ 2 yr; 27 Ϯ 1 vs. 26 Ϯ 2 ml·kg Ϫ1 ·min Ϫ1Ϫ1 ). Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively. Twenty-one NAFLD patients completed either 16 wk of supervised moderate-intensity exercise training (n ϭ 13) or conventional care (n ϭ 8). Differences between NAFLD and controls were compared using independent t-tests and effects of interventions by analysis of covariance. NAFLD patients had higher liver fat [11.6% (95% CI ϭ 7.4, 18.1), P Ͻ 0.0005] and VAT [1.6 liters (95% CI ϭ 1.2, 2.0), P Ͻ 0.0001] than controls and exhibited impaired FMD compared with controls [Ϫ3.6% (95% CI ϭ Ϫ4.9, Ϫ2.2), P Ͻ 0.0001]. FMD was inversely correlated with VAT (r ϭ Ϫ0.54, P ϭ 0.001) in NAFLD, although the impairment in FMD remained following covariate adjustment for VAT [3.1% (95% CI ϭ 1.8, 4.5), P Ͻ 0.001]. Exercise training, but not conventional care, significantly improved V O2 peak [9.1 ml·kg Ϫ1 ·min Ϫ1 (95% CI ϭ 4.1, 14.1); P ϭ 0.001] and FMD [3.6% (95% CI ϭ 1.6, 5.7), P ϭ 0.002]. Endothelial dysfunction in NAFLD cannot be fully explained by excess VAT but can be reversed with exercise training; this has potential implications for the primary prevention of CVD in NAFLD. nonalcoholic fatty liver disease; flow-mediated dilation; cardiovascular risk; exercise training NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is a disease spectrum ranging from simple steatosis, progressing to necroinflammatory changes (nonalcoholic steatohepatitis) and in a subset, to cirrhosis, fibrosis, and end-stage liver disease (20). NAFLD is the most common form of chronic liver disease in Western society, affecting 20 -30% of the general population (6) and up to ϳ60% of individuals with type 2 diabetes mellitus (43). NAFLD is regarded as the hepatic manifestation of the metabolic syndrome, coexisting with multiple cardiometabolic risk factors, including obesity, insulin resistance, hypertension, and dyslipidemia (34).NAFLD increases the risk of chronic liver disease, yet epidemiological studies suggest that cardiovascular disease (CVD) accounts for more deaths in NAFLD than liver disease, some reporting CVD to be the leading cause of mortality (10,23,34). Indeed, there is strong evidence that NAFLD patients are at greater risk of CVD than controls and that NAFLD is an independent predictor of cardiovascular morbidity and mortality ...

Exercise Training as Treatment of Nonalcoholic Fatty Liver Disease

“…Nine randomized control trials and four uncontrolled studies have investigated the effects of aerobic training in NAFLD (Table 1) [9][10][11][19][20][21][22][23][24][25][26][27][28]. All of the studies included at least one aerobic training experimental group, with three studies containing multiple aerobic training groups of differing exercise intensities [11,22,24].…”

“…Maximum heart rate (MHR), heart rate reserve (HRR), maximal predicted heart rate (MPHR), metabolic equivalent of task (MET), or VO 2max were used to determine exercise intensity prescriptions-where intensities range from light to moderate (30-39% of HRR, 57-63% of HRR, 2.0-3.9 METs, and 37-45% of VO 2max ) moderate (40-59% of HRR, 64-76% of HRR, 4.0-5.9 METs, and 46-63% of VO 2max ), and vigorous (60-89% of HRR, 77-95% of HRR, 6.0-8.4 METs, and 64-90% of VO 2max ) [9][10][11][19][20][21][22]24,26,27,29]. Exercise modalities included recreational walking, treadmill running, cycle ergometry, cross-training, rowing, and rhythmic exercise [10,11,[20][21][22][23][24][25][26][27]. Six studies used single modality exercise, while four studies used a multitude of exercise modalities [9][10][11][20][21][22][23][25][26][27].…”

“…Exercise modalities included recreational walking, treadmill running, cycle ergometry, cross-training, rowing, and rhythmic exercise [10,11,[20][21][22][23][24][25][26][27]. Six studies used single modality exercise, while four studies used a multitude of exercise modalities [9][10][11][20][21][22][23][25][26][27]. Only two studies did not specify aerobic training.…”

“…Only two studies did not specify aerobic training. Exercise intervention lengths ranged from one week to one year, with the most commonly used duration as 16-weeks [9,[19][20][21][22][23]25,26,28]. Frequency of exercise dosage ranged from three times per week for 30 min per day to seven times per week for 60 min per day [19][20][21]25,26].…”

The benefits of exercise for patients with non-alcoholic fatty liver disease

“…Given that cardiovascular disease is the primary cause of mortality in patients with NAFLD, the benefits of exercise extend beyond steatosis. There is substantial evidence for exercise benefiting the secondary vascular and metabolic co-morbidities associated with NAFLD, including insulin resistance, dyslipidemia, inflammation, hypertension [9] and endothelial dysfunction [16,26], which reduces the risk of liverrelated and cardiovascular morbidity and mortality. Indeed, a one Metabolic Equivalent improvement in cardiorespiratory fitness (3.5 ml/kg/min) is associated with a 13 and 15% reduction in all-cause mortality and risk of cardiovascular events, respectively [27].…”