title: Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza.
abstract: In response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57Bl/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and carnitine species. These metabolic adaptations coincided with a depression in hepatic long chain β-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in β-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection.
authors: Metabolism, Infection and Immunity Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Tatyana N
authors: TN
authors: Tarasenko
authors: Center for Mitochondrial and Epigenomic Medicine, Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors: Larry N
authors: LN
authors: Singh
authors: Metabolism, Infection and Immunity Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Milani
authors: M
authors: Chatterji-Len
authors: Office of Research Services, Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA.
authors: Patricia M
authors: PM
authors: Zerfas
authors: Biochemical Genetics and Metabolism Laboratory, Children's National Medical Center, Washington, DC, USA.
authors: Kristina
authors: K
authors: Cusmano-Ozog
authors: Metabolism, Infection and Immunity Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: peter.mcguire@nih.gov.
authors: Peter J
authors: PJ
authors: McGuire
keywords: Fatty acids; Influenza; Innate immune response; Metabolism; β-oxidation