Ketone body therapy protects from lipotoxicity and acute liver failure upon Ppar α deficiency

Abstract

Acute liver failure (ALF) is a severe and rapid liver injury, often occurring without any preexisting liver disease, which may precipitate multiorgan failure and death. ALF is often associated with impaired-oxidation and increased oxidative stress (OS), characterized by elevated levels of hepatic reactive oxygen species (ROS) and lipid peroxidation (LPO) products. Peroxisome proliferator-activated receptor (PPAR) has been shown to confer hepatoprotection in acute and chronic liver injury, at least in part, related to its ability to control peroxisomal and mitochondrial-oxidation. To study the pathophysiological role of PPAR in hepatic response to high OS, we induced a pronounced LPO by treating wild-type and Ppar-deficient mice with high doses of fish oil (FO), containing n-3 polyunsaturated fatty acids. FO feeding of Ppardeficient mice, in contrast to control sunflower oil, surprisingly induced coma and death due to ALF as indicated by elevated serum alanine aminotransferase, aspartate aminotransferase, ammonia, and a liver-specific increase of ROS and LPO-derived malondialdehyde. Reconstitution of PPAR specifically in the liver using adeno-associated serotype 8 virus-PPAR in Ppar-deficient mice restoredoxidation and ketogenesis and protected mice from FO-induced lipotoxicity and death. Interestingly, administration of the ketone body-hydroxybutyrate prevented FO-induced ALF in Ppar-deficient mice, and normalized liver ROS and malondialdehyde levels. Therefore, PPAR protects the liver from FO-induced OS through its regulatory actions on ketone body levels. Hydroxybutyrate treatment could thus be an option to prevent LPO-induced liver damage.