The role of triiodothyronine-induced substrate cycles in the hepatic response to overnutrition: thyroid hormone as an antioxidant.
Overnutrition, by generating reactive oxygen species (ROS), produces oxidative stress - an important cause of cellular injury. In the liver, overnutrition begins in the perivenous hepatocytes. To prevent injury, cells must protect themselves against ROS accumulation. Overnutrition also activates the enzyme deiodinase-1 (D1), which catalyzes the conversion of T4 to T3. D1 is primarily located in the PV region of the liver. Thyroid hormone is known to generate substrate cycling. The hypothesis of this paper is that a nutrient-induced increase in intracellular T3 acts as an antioxidant by inducing substrate cycles that reduce ROS accumulation. These cycles do this by: (i) reducing ROS formation by hydrolyzing excess ATP, thus enhancing oxidative phosphorylation and reducing the proton motive force on the electron transport chain (ETC), and; (ii) enhancing the removal (reduction) of ROS by producing the NADPH required for regeneration of reduced glutathione, a potent endogenous antioxidant. Oxidative stress is an important factor in the etiology of a number of hepatic injuries, including nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. In the latter, the frequency of mutations in thyroid hormone receptors (TRs) supports the concept that thyroid hormone acts as a tumor suppressor by reducing oxidative stress. This paper reviews the substrate cycles involved in this process. It also describes other mechanisms that permit rapid availability of T3 to cells undergoing oxidative stress.
Grant
Neville
N
Department of Medicine, Washington University School of Medicine, David P Wohl Jr., Hospital, 4960 Children's Pl sixth floor, St. Louis, MO, USA. grantn@newmexico.com
D000975:Antioxidants / Q000494:pharmacology*; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology*; D008954:Models, Biological; D044343:Overnutrition / Q000503:physiopathology*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014284:Triiodothyronine / Q000502:physiology*
D000975:Antioxidants; D017382:Reactive Oxygen Species; D014284:Triiodothyronine