Deletion of Hepatocellular eNOS Impairs Exercise-Induced Improvements in Hepatic Mitochondrial Function

Abstract Text

Deletion of hepatocellular eNOS impairs exercise-induced improvements in hepatic mitochondrial function

Rory P. Cunningham^1,3, Mary P. Moore^1,3, Grace M. Meers^{1, 3}, Vivien Jepkemoi¹, R. Scott Rector^1,2,3

¹Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri 65212, USA; ²Departments of Medicine-Division of Gastroenterology and Hepatology, ³Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA;

Introduction: The mechanisms responsible for exercise-induced improvements in hepatic mitochondrial function remain unresolved. One potential mediator of these beneficial changes may be hepatocellular endothelial nitric oxide synthase (eNOS). Here, we examine whether hepatocellular eNOS is required for the exercise-induced improvements in the liver.

Methods: At 10 weeks of age, eNOS floxed (eNOS^fl/fl) and hepatic-specific eNOS knockout (eNOS^hep-/-) mice were given access to voluntary running wheels (VWR) or kept sedentary (SED), and fed a control diet (10% fat) for 10 weeks (n = 9-14/grp).

Results: Body weight, body fat, and food intake did not differ between eNOS^fl/fl and eNOS^hep-/- mice, while VWR reduced body fat % and increased food intake, compared to SED (p<0.05), regardless of genotype. There was no difference in average daily distance ran between eNOS^fl/fl and eNOS^hep-/- mice (6.38 km vs 6.31 km/d). eNOS^hep-/- mice had lower complete and total 1-¹⁴C-palmitate oxidation compared to eNOS^fl/fl mice (main effect for genotype, p=0.03), as well as reduced state 3-complex I+II hepatic mitochondrial respiration (main effect for genotype, p=0.03). In addition, VWR significantly increased complete 1-¹⁴C-palmitate oxidation to CO₂ (81%) and total 1-¹⁴C-palmitate oxidation (17%) vs SED in eNOS^fl/fl mice (p<0.05); however, this VWR-induced increase in palmitate oxidation was completely absent in VWR-eNOS^hep-/- mice vs SED-eNOS^hep-/-.

Conclusion: Here we demonstrate for the first time that hepatocellular eNOS may be required for the exercise-induced adaptations to hepatic mitochondrial function. Further studies are necessary to determine the mechanisms by which deletion of eNOS regulates hepatic mitochondrial adaptations to exercise. Support: VA Merit Grant I01BX003271-03 (R.S.R.)