title: VASCULAR AND METABOLIC ADAPTATIONS TO EXERCISE IN NON-ALCOHOLIC FATTY LIVER DISEASE
Creators: name: Pugh, CJA
Publisher: name: Liverpool John Moores University
Year: 2011

description: Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of fat in the liver and is associated with liver-related morbidity and mortality. Nevertheless, the leading cause of death in these patients is cardiovascular disease (CVD). Excess abdominal visceral adipose tissue (VAT) is frequently expressed in NAFLD and is considered a pivotal feature in the pathogenesis of NAFLD which is predictive of CVD. Endothelial dysfunction is an early manifestation in the development of atherosclerosis and is characterised by a diminished bioavailabilty of the anti-atherogenic molecule NO, which is secreted by the endothelium of all blood vessels throughout the vascular tree. Limited pharmacological treatment is available to reduce hepatic fat, therefore, lifestyle modification interventions comprised of structured exercise and diet are recommended as a non-pharmacological management strategy to reduce hepatic fat in NAFLD. The primary aim of this thesis was to explore nitric oxide (NO)-mediated endothelial function at different levels of the vascular tree in NAFLD patients and to establish whether supervised exercise training has a sustained therapeutic impact on endothelial function. Thirty-two NAFLD patients (21 males, 11 females, 48±2yrs, BMI 31±1kg/m2) and eighteen matched controls (8 males, 10 females, 48±2yrs, BMI 30±1kg/m2) underwent magnetic resonance imaging (MRI) to quantify abdominal VAT and proton magnetic resonance spectroscopy (1H-MRS) to determine intrahepatocellular triglyceride content (IHTC). Brachial artery flow mediated dilatation (FMD) (as an index of endothelial NO function) was also assessed. IHTC (27.2±3.0 vs. 2.9±0.4%) and abdominal VAT (5.4±0.3vs. 3.4±0.2 l) were elevated in NAFLD patients when compared with controls (P&lt;0.0005). FMD was significantly impaired in NAFLD patients when compared with controls (4.8±0.3 vs. 8.3±0.7%, P&lt;0.0005). A significant inverse correlation was observed between FMD and abdominal VAT (r = -0.48, P=0.01) in NAFLD patients, but no relationship was observed between FMD and IHTC (P&gt;0.05). Impairment in FMD remained in NAFLD patients following independent covariate adjustment for abdominal VAT (5.0±0.5 vs. 7.3±0.7%, P=0.01). These findings indicate that excess IHTC and abdominal VAT do not explain endothelial dysfunction in NAFLD. Twenty NAFLD patients were randomly assigned to either 16-weeks of supervised moderate intensity (30-60% HRR, 30-45 min, 3-5 times per week) exercise training (n=13, 50±3yrs, BMI 30±1kg/m2) or to 16-weeks of conventional care lifestyle advice (n=7, 47±6yrs, BMI 31±2kg/m2). Supervised exercise training induced a greater improvement in FMD when compared with conventional care (3.6±0.6 vs. 0.3±0.8%, P=0.004). There was no significant difference between the effect of exercise and conventional care on IHTC or abdominal VAT (P&gt;0.05). These data suggest that supervised exercise training is an effective management strategy in NAFLD capable of improving conduit artery endothelial function independent of IHTC and abdominal VAT. In order to explore the longevity of the exercise-induced improvements in conduit artery endothelial function, a 12-month follow up assessment was performed in 9 of the NAFLD patients (5 males, 4 females, 50±5yrs, BMI 30±1kg/m2) who completed the 16-week supervised exercise training intervention. The exercise-induced improvement in FMD (5.1±0.8 vs. 7.9±0.8%; P=0.004) was abolished 12 months following the cessation of supervised exercise training (7.9±0.8 vs.5.0±0.5%; P=0.02), returning to a similar level observed at baseline (5.1±0.8 vs. 5.0±0.5%; P=0.95).These findings indicate that in order to chronically sustain exercise-induced improvements in endothelial function in NAFLD patients, long-term exercise supervision and guidance is required. Cutaneous NO-mediated microvessel function reflects generalised microvascular function and provides a translational model to investigate pre-clinical disease, but has not been previously investigated in NAFLD. NO-mediated vasodilatation in the cutaneous microvessels was examined in 13 NAFLD patients (7 males, 6 females, 50±3yrs, BMI 31±1kg/m2) and 7 matched controls (3 males, 4 females, 48±4yrs, BMI 30±2 kg/m2). Microdialysis fibres were embedded into the skin of the forearm and laser Doppler probes placed over these sites. Both sites were then heated to 42°C, with saline solution infused in one probe and L-NG-monomethyl arginine (L-NMMA) through the second. Following baseline assessment, 11 NAFLD patients were randomly assigned to 16-weeks of supervised moderate intensity exercise training (n=6, 45±5yrs, BMI 31±1kg/m2) or to 16-weeks of conventional care (n=5, 51±3yrs, BMI 30±21kg/m2). The NO contribution to skin blood flow in response to incremental heating was not different between NAFLD patients and controls (P=0.47) at baseline. However, significant differences were evident in NO contribution between the exercise training and conventional care group (P=0.01), suggesting that supervised exercise training improves cutaneous NO-mediated microvascular endothelial function in NAFLD patients. This thesis suggests that supervised exercise training has a direct therapeutic impact on endothelial function in NAFLD which may decrease the risk of future heart disease and stroke. As a cardioprotective management strategy in NAFLD, exercise training is superior to that of current conventional care pathways, however, in order to chronically sustain the exercise-induced improvements in endothelial function, long term exercise supervision and guidance is required.