Christopher J. A. Pugh, Victoria S. Sprung, Graham J. Kemp, Paul Richardson, Fariba Shojaee-Moradie, A. Margot Umpleby, Daniel J. Green, N. Timothy Cable, Helen Jones, Daniel J. Cuthbertson

Non-alcoholic 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 two-fold: to examine i) the association between liver fat, visceral adipose tissue (VAT) and endothelial dysfunction in obese NAFLD patients and, ii) 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 (VO2peak) (48±2 vs. 47±2y; 27±1 vs. 26±2ml.kg(-1).min(-1)). Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively. Twenty-one NAFLD patients completed either 16-weeks of supervised moderate-intensity exercise training (n=13) or conventional care (n=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=7.4, 18.1), P<0.0005] and VAT [1.6L (95%CI=1.2, 2.0), P<0.0001] than controls and exhibited impaired FMD compared with controls [-3.6% (95%CI=-4.9,-2.2), P<0.0001]. FMD was inversely correlated with VAT (r= -0.54, P=0.001) in NAFLD, although the impairment in FMD remained following covariate adjustment for VAT [3.1% (95%CI= 1.8, 4.5), P<0.001]. Exercise training, but not conventional care, significantly improved VO2peak [9.1ml/kg(-1)/min(-1) (95%CI=4.1, 14.1); P=0.001] and FMD [3.6% (95%CI=1.6, 5.7), P=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.