A Western diet induced NAFLD in LDLR(-/)(-) mice is associated with reduced hepatic glutathione synthesis.
The liver is the only tissue that has been demonstrated directly to secrete glutathione into the plasma. The present experiments were carried out to determine whether extrahepatic tissues secrete the reduced form of glutathione (GSH) as well. Phorone, a compound that depletes glutathione through glutathione S-transferase-dependent conjugation with GSH, was administered to fasted rats in a dose of 250 mg/kg. Two hours later, glutathione concentrations were reduced to the following: liver, 2%; plasma, 17%; and skeletal muscle, 63%. This showed that plasma and muscle glutathione were not depleted to the same extent as liver glutathione. Glutathione concentration in plasma from the hepatic vein was not higher than concentrations in plasma from the portal vein and from the aorta, indicating that the depleted liver was not releasing glutathione into the plasma. Total glutathione and GSH were higher in plasma from the femoral vein than in plasma from the aorta under these same conditions. This indicates that the leg releases GSH under conditions of absent hepatic GSH release when plasma glutathione concentrations are decreased. These results suggest that muscle secretes GSH into the extracellular space and raise the possibility that other tissues secrete GSH as well. Further studies will be required to determine whether GSH release by extrahepatic tissues is affected by the plasma glutathione concentration.