| First Author | Pawlak M | Year | 2015 |
| Journal | Mol Endocrinol | Volume | 29 |
| Issue | 8 | Pages | 1134-43 |
| PubMed ID | 26087172 | Mgi Jnum | J:232954 |
| Mgi Id | MGI:5780506 | Doi | 10.1210/me.2014-1383 |
| Citation | Pawlak M, et al. (2015) Ketone Body Therapy Protects From Lipotoxicity and Acute Liver Failure Upon Pparalpha Deficiency. Mol Endocrinol 29(8):1134-43 |
| abstractText | 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 beta-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)alpha 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 beta-oxidation. To study the pathophysiological role of PPARalpha in hepatic response to high OS, we induced a pronounced LPO by treating wild-type and Pparalpha-deficient mice with high doses of fish oil (FO), containing n-3 polyunsaturated fatty acids. FO feeding of Pparalpha-deficient 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 PPARalpha specifically in the liver using adeno-associated serotype 8 virus-PPARalpha in Pparalpha-deficient mice restored beta-oxidation and ketogenesis and protected mice from FO-induced lipotoxicity and death. Interestingly, administration of the ketone body beta-hydroxybutyrate prevented FO-induced ALF in Pparalpha-deficient mice, and normalized liver ROS and malondialdehyde levels. Therefore, PPARalpha protects the liver from FO-induced OS through its regulatory actions on ketone body levels. beta-Hydroxybutyrate treatment could thus be an option to prevent LPO-induced liver damage. |
