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.

The liver is a metabolic and immunologic organ: A reconsideration of metabolic decompensation due to infection in inborn errors of metabolism (IEM)

“…Previous work by our group demonstrated a depression of urea cycle enzymes and fatty acid oxidation during influenza infection in wild-type mice in the absence of hepatocyte death [22,23]. These changes in metabolic reserve were linked to the actions of inflammatory cytokines on hepatocytes, particularly TNFα [23]. By our definition, metabolic decompensation is not just limited to patients with IEM.…”

“…valproic acid induced steatosis and acute liver toxicity) [21]. Whether immune activation in response to infection also results in a toxic insult to the IEM liver causing metabolic decompensation is just beginning to be explored [22,23].…”

“…Significant hepatotoxicity has been noted in many experimental systems and clinical states whose pathology is mediated by cytokines: paraneoplastic phenomena, limb ischemia, sepsis and endotoxemia [45][46][47][48]. The hepatic biochemical abnormalities observed during these systemic inflammatory reactions in non-IEM patients are mediated by inflammatory cytokines such IL-1, IL-6 and TNFα [23,49,50] and may include hypoglycemia, lactic acidosis and hepatic encephalopathy [51,52]. In addition to mediating organ dysfunction, cytokines may serve as outcome markers; IL-6, IL-8, IL-10 and TNF-α concentrations are accurate predictors of hepatic dysfunction [53,54].…”

“…As suggested above, metabolic decompensation is not unique to IEM. In healthy livers, low levels of inflammatory cytokines promote changes in metabolic reserve to cope with the challenges to homeostasis brought about by infection [22,23]. As inflammation increases, organs may progress along a continuum of dysfunction and metabolic decompensation.…”

“…To address these fundamental questions regarding metabolic reserve and metabolic decompensation in response to viral infection, we established a model system using mouse adapted PR8 influenza combined with pair-feeding to minimize the effects of differences in food intake [22,23]. In our model, although the liver is distant from the site of PR8 influenza infection (i.e.…”