title: Short-term exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease.
abstract: Increased hepatocyte apoptosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and contributes to the profibrogenic state responsible for the progression to nonalcoholic steatohepatitis (NASH). Strategies aimed at reducing apoptosis may result in better outcomes for individuals with NAFLD. We therefore examined the effect of a short-term exercise program on markers of apoptosis-plasma cytokeratin 18 (CK18) fragments, alanine aminotransferase (ALT), aspartate aminotransferase (AST), soluble Fas (sFas), and sFas ligand (sFasL)-in 13 obese individuals with NAFLD [body mass index 35.2 ± 1.2 kg/m(2), >5% intrahepatic lipid (IHL) assessed by (1)H-MR spectroscopy]. Exercise consisted of treadmill walking for 60 min/day on 7 consecutive days at ∼85% of maximal heart rate. Additionally, subjects underwent an oral glucose tolerance test and a maximal oxygen consumption (Vo(2max)) test before and after the exercise intervention. The Matsuda index was used to assess insulin sensitivity. We observed significant decreases in CK18 fragments (558.4 ± 106.8 vs. 323.4 ± 72.5 U/l, P < 0.01) and ALT (30.2 ± 5.1 vs. 24.3 ± 4.8 U/l, P < 0.05), and an increase in whole body fat oxidation (49.3 ± 6.1 vs. 69.4 ± 7.1 mg/min, P < 0.05), while decreases in circulating sFasL approached statistical significance (66.5 ± 6.0 vs. 63.0 ± 5.7 pg/ml, P = 0.06), as did the relationship between percent change in circulating CK18 fragments and ALT (r = 0.55, P = 0.05). We also observed a significant correlation between changes in fat oxidation and circulating sFasL (rho = -0.65, P < 0.05). There was no change in IHL following the intervention (18.2 ± 2.5 vs. 17.5 ± 2.1%, NS). We conclude that short-term exercise reduces a circulatory marker of hepatocyte apoptosis in obese individuals with NAFLD and propose that changes in the proapoptotic environment may be mediated through improved insulin sensitivity and increased oxidative capacity.
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Ciaran E
authors.initials: CE
authors.lastname: Fealy
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Haus
authors.forename: Thomas P J
authors.initials: TP
authors.lastname: Solomon
authors.forename: Mangesh
authors.initials: M
authors.lastname: Pagadala
authors.forename: Chris A
authors.initials: CA
authors.lastname: Flask
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: McCullough
authors.forename: John P
authors.initials: JP
authors.lastname: Kirwan
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D017209:Apoptosis / Q000502:physiology*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D026241:Exercise Movement Techniques; D005223:Fats / Q000378:metabolism; D005234:Fatty Liver / Q000628:therapy*; D005260:Female; D005951:Glucose Tolerance Test; D006339:Heart Rate / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D053538:Keratin-18 / Q000097:blood; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D010101:Oxygen Consumption / Q000502:physiology; D016138:Walking / Q000502:physiology*; D019014:fas Receptor / Q000097:blood
chemical_list: D015415:Biomarkers; C491901:FAS protein, human; D005223:Fats; C488421:KRT18 protein, human; D053538:Keratin-18; D019014:fas Receptor; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase