Mitochondria in steatohepatitis

For the first time in history, populations in affluent countries may concom itantly indulge in rich food and physical idleness. Various combinations of obesity, diabetes, and hypertriglyceridemia, with insulin resistance as th e common feature, cause hepatic steatosis, which can trigger necroinflammat ion and fibrosis. Patients with "primary" steatohepatitis exhibit ultrastru ctural mitochondrial lesions, decreased activity of respiratory chain compl exes, and have impaired ability to resynthesize ATP after a fructose challe nge. Mitochondria play a major role in fat oxidation and energy production but also leak reactive oxygen species (ROS) and are the main cellular sourc e of ROS. In patients with steatosis, mitochondrial ROS may oxidize hepatic fat deposits, as suggested in animal models. Lipid peroxidation products i mpair the flow of electrons along the respiratory chain, which may cause ov erreduction of respiratory chain components, further increasing mitochondri al ROS formation and lipid peroxidation. Another vicious circle could invol ve ROS-induced depletion of antioxidants, impairing ROS inactivation. Blood vitamin E is decreased in some obese children with steatohepatitis, and se rum transaminases improve after vitamin E supplementation. Steatohepatitis is also caused by alcohol abuse, drugs, and other causes. In "secondary" st eatohepatitis, mitochondrial ROS formation is further increased as the caus ative disease itself directly increases ROS or first impairs respiration, w hich secondarily increases mitochondrial ROS formation. This "second hit" c ould cause more lipid peroxidation, cytokine induction, Fas ligand inductio n, and fibrogenesis than in primary steatohepatitis.