title: The presence of the ovary prevents hepatic mitochondrial oxidative stress in young and aged female mice through glutathione peroxidase 1.
abstract: BACKGROUND
  For unknown reasons a woman's risk for developing Metabolic Syndrome (MetS) increases dramatically with age and/or loss of ovarian function. The MetS is characterized by hepatic insulin resistance (IR), which is strongly associated with intrahepatic lipid (IHL) accumulation, mitochondrial dysfunction, and oxidative stress. Although circumstantial evidence suggests that the endocrine function of the ovary can directly impact hepatic mitochondrial function, this hypothesis remains untested. Thus, the purpose of this study was to assess the influence of age and secretory function of the ovary on mechanisms that regulate hepatic mitochondrial function.
  
  
  METHODS
  Adult (10 week-old) and aged (88 week-old) female C57BL/6 mice were separated into two groups to undergo bilateral ovariectomy (OVX) or control surgery (SHAM). Eight weeks after surgery hepatic tissue was removed for measurements of total IHL and fatty acid species within hepatic triglycerides, mitochondrial function, and reactive oxygen species (ROS) production.
  
  
  RESULTS
  Hepatic IHL content was not affected by OVX, but was increased by age. OVX had no effect on mitochondrial respiration, however, hepatic mitochondria from aged mice had lower O2 consumption, lower complex IV and higher complex I content. Mitochondrial H2O2 production was highest in OVX groups and exacerbated by age, while mitochondrial lipid peroxidation was highest in the aged mice and exacerbated by OVX. Regardless of age, OVX resulted in lower mitochondrial content of antioxidant glutathione peroxidase 1 (Gpx1). Isolated liver tissue from a sub-set of animals were acutely treated with conditioned ovarian media which increased Gpx1 mRNA expression compared to vehicle treated liver tissue.
  
  
  CONCLUSIONS
  Ovarian secretory function is necessary for the maintenance of hepatic ROS buffering capacity in the mitochondria, while age significantly influences mitochondrial respiration. These data suggest that when age is coupled with loss of ovarian function there is an increased risk for developing hepatic mitochondrial dysfunction, which may influence the onset of metabolic disease. Thus, in females there is critical organ cross-talk occurring between hepatic tissue and the ovary that impacts hepatic mitochondrial function.
authors.affiliation: University of Maryland, Department of Kinesiology, College Park, MD 20742, United States.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Valencia
authors.affiliation: University of Maryland, Department of Nutrition, College Park, MD 20742, United States.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Schappal
authors.affiliation: University of Missouri, Department of Nutrition and Exercise Physiology Medicine, Division of Gastroenterology and Hepatology, Columbia, MO 65201, United States; Harry S Truman Memorial VA Hospital, Research Service, Columbia, MO 65201, United States.
authors.forename: E Matthew
authors.initials: EM
authors.lastname: Morris
authors.affiliation: University of Missouri, Department of Nutrition and Exercise Physiology Medicine, Division of Gastroenterology and Hepatology, Columbia, MO 65201, United States; Harry S Truman Memorial VA Hospital, Research Service, Columbia, MO 65201, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Thyfault
authors.affiliation: University of Minnesota, Programs in Physical Therapy and Rehabilitation Science, Department of Physical Medicine and Rehabilitation, Minneapolis, MN 55455, United States.
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Lowe
authors.affiliation: University of Maryland, Department of Kinesiology, College Park, MD 20742, United States. Electronic address: spangenburge14@ecu.edu.
authors.forename: Espen E
authors.initials: EE
authors.lastname: Spangenburg
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005979:Glutathione Peroxidase / Q000235:genetics / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism*; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010101:Oxygen Consumption / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D005227:Fatty Acids; D012333:RNA, Messenger; D014280:Triglycerides; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
keywords: Aging; Gpx1; Liver; Mitochondrial function; Ovariectomy; Oxidative stress