Early interleukin-6 enhances hepatic ketogenesis in APP SWE/PSEN1dE9 mice via 3-hydroxy-3-methylglutary-CoA synthase 2 signaling activation by p38/nuclear factor κB p65

Neurobiol Aging. 2017 Aug;56:115-126. doi: 10.1016/j.neurobiolaging.2017.04.014. Epub 2017 Apr 26.


Alzheimer's disease (AD) is considered a multifactorial disease that affects the central nervous system and periphery. A decline in brain glucose metabolism is an early feature of AD and is accompanied by a phenotypic shift from aerobic glycolysis to ketogenesis. The liver is responsible for the generation of the ketone body. However, the mechanism that underlies hepatic ketogenesis in AD remains unclear. Here, we investigated hepatic ketogenesis during the early stage of AD pathogenesis in amyloid precursor protein (APPSWE) and presenilin (PSEN1dE9) (APP/PS1) mice. We observed that β-hydroxybutyric acid was increased in the brain of the postmortem mild cognitive impairment and AD subjects and in 3-month-old APP/PS1 AD mice. A rise in 3-hydroxy-3-methylglutary-CoA synthase 2 (HMGCS2), a key enzyme for catalyzing β-hydroxybutyric acid production, was observed in early AD mice. We further showed that proinflammatory cytokines were activated in the liver prior to their activation in the brain of 3-month-old APP/PS1 mice. Among the cytokines, interleukin-6 significantly activated HMGCS2 through the binding of nuclear factor κB (NF-κB) p65 to the HMGCS2 promoter. Additionally, interleukin-6 stimulated phosphorylation of p38 mitogen activated protein kinases, an upstream molecule for NF-κB p65 signaling. We have demonstrated that a hepatic inflammatory factor enhances ketogenesis through HMGCS2 signaling activation by p38/NF-κB p65. These results provide a novel peripheral metabolic mechanism for enhanced ketone production and suggest a plausible early AD phenotype to diagnose AD.

Keywords: Alzheimer's disease; Inflammation; Ketone body; Liver; Metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / metabolism
  • Animals
  • Biomarkers / metabolism
  • Brain / metabolism
  • Hydroxybutyrates / metabolism
  • Hydroxymethylglutaryl-CoA Synthase / metabolism*
  • Interleukin-6 / physiology*
  • Ketone Bodies / metabolism*
  • Liver / metabolism*
  • Mice, Transgenic
  • NF-kappa B / physiology*
  • Phosphorylation / genetics
  • Signal Transduction / genetics*
  • Signal Transduction / physiology*
  • p38 Mitogen-Activated Protein Kinases / physiology*


  • Biomarkers
  • Hydroxybutyrates
  • Interleukin-6
  • Ketone Bodies
  • NF-kappa B
  • HMGCS2 protein, mouse
  • Hydroxymethylglutaryl-CoA Synthase
  • p38 Mitogen-Activated Protein Kinases