title: Ketone Body Therapy Protects From Lipotoxicity and Acute Liver Failure Upon Pparα 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 β-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)α 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 β-oxidation. To study the pathophysiological role of PPARα in hepatic response to high OS, we induced a pronounced LPO by treating wild-type and Pparα-deficient mice with high doses of fish oil (FO), containing n-3 polyunsaturated fatty acids. FO feeding of Pparα-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 PPARα specifically in the liver using adeno-associated serotype 8 virus-PPARα in Pparα-deficient mice restored β-oxidation and ketogenesis and protected mice from FO-induced lipotoxicity and death. Interestingly, administration of the ketone body β-hydroxybutyrate prevented FO-induced ALF in Pparα-deficient mice, and normalized liver ROS and malondialdehyde levels. Therefore, PPARα protects the liver from FO-induced OS through its regulatory actions on ketone body levels. β-Hydroxybutyrate treatment could thus be an option to prevent LPO-induced liver damage.
authors.affiliation: European Genomic Institute for Diabetes, Inserm UMR1011, and University Lille, F-59000 Lille Cédex, France; and Institut Pasteur de Lille, F-59019 Lille Cédex, France.
authors.forename: Michal
authors.initials: M
authors.lastname: Pawlak
authors.affiliation: European Genomic Institute for Diabetes, Inserm UMR1011, and University Lille, F-59000 Lille Cédex, France; and Institut Pasteur de Lille, F-59019 Lille Cédex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Baugé
authors.affiliation: European Genomic Institute for Diabetes, Inserm UMR1011, and University Lille, F-59000 Lille Cédex, France; and Institut Pasteur de Lille, F-59019 Lille Cédex, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Lalloyer
authors.affiliation: European Genomic Institute for Diabetes, Inserm UMR1011, and University Lille, F-59000 Lille Cédex, France; and Institut Pasteur de Lille, F-59019 Lille Cédex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lefebvre
authors.affiliation: European Genomic Institute for Diabetes, Inserm UMR1011, and University Lille, F-59000 Lille Cédex, France; and Institut Pasteur de Lille, F-59019 Lille Cédex, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000737:chemistry; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D007657:Ketone Bodies / Q000737:chemistry*; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D017114:Liver Failure, Acute / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D047493:PPAR alpha / Q000172:deficiency* / Q000378:metabolism*; D020675:Peroxisomes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D007657:Ketone Bodies; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D014280:Triglycerides; D020155:3-Hydroxybutyric Acid