BackgroundLifestyle interventions focusing on weight loss remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management. Despite this, the weight losses achieved in research trials are not easily replicated in the clinic and there is an urgent need for therapies independent of weight loss. Aerobic exercise is not well sustained and the effectiveness of the better tolerated resistance exercise upon liver lipid and mediators of liver lipid has not been assessed.MethodsSedentary adults with clinically defined NAFLD were assigned to 8 weeks of resistance exercise (n=11) or continued normal treatment (n=8).Results8 weeks of resistance exercise elicited a 13% relative reduction in liver lipid (14.0±9.1 vs 12.2±9.0; p<0.05). Lipid oxidation (submaximal RQ ∆ −0.020±0.010 vs −0.004±0.003; p<0.05), glucose control (−12% vs +12% change AUC; p<0.01) and homeostasis model assessment insulin resistance (5.9±5.9 to 4.6±4.6 vs 4.7±2.1 to 5.1±2.5; p<0.05) were all improved. Resistance exercise had no effect on body weight, visceral adipose tissue volume, or whole body fat mass (p>0.05).ConclusionThis is the first study to demonstrate that resistance exercise specifically improves NAFLD independent of any change in body weight. These data demonstrate that resistance exercise may provide benefit for the management for non-alcoholic fatty liver, and the long-term impact of this now requires evaluation.

When exercising to comparable levels to normal controls, CFS patients exhibit profound abnormality in bioenergetic function and response to it. Although exercise intervention is the logical treatment for patients showing acidosis, any trial must exclude subjects who do not initiate exercise as they will not benefit. This potentially explains previous mixed results in CFS exercise trials.

Aggregation of the high-affinity immunoglobulin E (IgE) receptor (FceRI), expressed on mast cells and basophils, initiates the immediate hypersensitivity reaction. Aggregated FceRI has been reported to rapidly migrate to lipid rafts in RBL-2H3 cells. We confirmed that aggregated FceRI is found in the lipid raft fractions of cellular lysates. Furthermore, we show that the cross-linked FceRI remains associated with detergent-resistant structures upon internalization. Previous morphological studies have reported that aggregated FceRI is endocytosed via clathrin-coated pits, which in general are not lipid raft associated. To address this apparent discrepancy, we employed siRNA to suppress expression of components of the clathrin-mediated internalization machinery, namely, clathrin heavy chain, and the AP-2 (a-adaptin or m2-subunit). Transferrin receptor (TfR) is endocytosed by a clathrin-mediated process and, as expected, each transfected siRNA caused a two to threefold elevation of TfR surface expression and almost completely inhibited its endocytosis. In contrast, there was no effect on surface expression levels of FceRI nor on the endocytosis of the dinitrophenyl-human serum albumin (DNP-HSA)/IgE/ FceRI complex. On the contrary, internalization of DNP-HSA/IgE/FceRI was inhibited by overexpression of a dominant-negative dynamin mutant. We conclude that internalization of cross-linked FceRI does not require the AP-2/clathrin complex but is dynamin-dependent and may be lipid raft mediated.

Cardiovascular system dysregulation in the form of autonomic dysfunction is common at all stages of the disease process in the autoimmune liver disease primary biliary cirrhosis (PBC) and associates with the symptom of fatigue. The mechanisms underpinning autonomic dysfunction in PBC are, however, at present unclear. In this study we set out to explore, for the first time, cardiac structure and function in PBC using impedance cardiography (ICG) and magnetic resonance methodologies. ICG was assessed beat to beat in response to orthostasis (by head-up tilt) in age and sex case-matched high-fatigue and low-fatigue PBC groups (assessed by Fatigue Impact Scale), normal control subjects (n = 15 each group) and a liver disease control cohort (primary sclerosing cholangitis). Cardiac structure and bioenergetics were examined in 15 of the PBC subjects and 8 of the normal control subjects by magnetic resonance spectroscopy and cine imaging. Capacity of the left ventricle to respond to orthostasis [left ventricular ejection time (LVET)] was impaired in PBC compared with matched normal control subjects (P = 0.05). This was a PBC-specific phenomenon unrelated to fatigue status. PBC patients exhibited significantly lower cardiac muscle phosphocreatine-to-ATP ratio (PCr/ATP ratio; measure of cardiac bioenergetic integrity) compared with control subjects (P < 0.01). PCr/ATP <1.6 (indicative of increased risk of death in cardiomyopathy) was present in 6/15 (40%) PBC patients (0/8 control subjects; P < 0.05). Cardiac structure and function were similar in all measures of left ventricular morphology between control subjects and PBC. The close relationship between PCr/ATP and LVET seen in normal subjects (r(2) = 0.6; P < 0.05) was lost in PBC patients, a finding compatible with myocardial dysfunction. Significant correlation was seen between fatigue severity in PBC and fall in cardiac output on orthostasis (r(2) = 0.25; P = 0.005). Our findings suggest the presence of altered myocardial function in PBC. Autonomic "dysfunction" may, rather than being an abnormal process, represent a compensatory mechanism to increase cardiac return to mitigate these effects.