The interplay between inflammation and FAOD in the pathogenesis of infection associated encephalopathy

Hiroshi Kido^1, Dengfu Yao^1,2, Dengbing Yao^1,3, Junji Chida¹, Min Yao^1,3

¹Division of Enzyme Chemistry, Institute for Enzyme Research, Tokushima University, Tokushima Japan
²School of Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
³School of Life Sciences, Key Laboratory of Neuroregeneration, Co-innovation Center of

Neuroregeneration, Nantong, Jiangsu, P.R. China

* email: kido@tokushima-u.ac.jp; Tel: +81 88 6337423

Infection-associated encephalopathy, in particular, influenza-associated encephalopathy (IAE) is characterized by persistent high fever, febrile convulsions, severe brain edema, multiple-organ failure and high mortality in otherwise apparently healthy infants. We previously reported that a large proportion of severe IAE patients with transiently elevated serum acylcarnitine ratios (C_16:0 + C_18:1)/C₂ >0.09 during high fever, exhibit a thermolabile phenotype of variants for [1055T>G/F352C] and [1055T>G/F352C] + [1102G>A/V368I] of carnitine palmitoyltransferase II (CPT II), a pivotal component of ATP generation through mitochondrial fatty acid β-oxidation (FAO). The kinetic characteristics of these CPT II variants show typical characteristics: (i) reduced activities due to significantly higher K_m values for L-carnitine and lower V_max values than those of WT CPT II; (ii) thermal instability; and (iii) short half-lives due to accelerated degradation by the proteasome compared with the WT. Since FAO is the major energy source at about 70% of the ATP generation particularly in endothelial cells and the brain capillary endothelium is characterized by a greater density of mitochondria than that of peripheral capillaries, the thermolabile CPT II variants may cause mitochondrial fuel utilization failure during high fever in the brain endothelial cells of IAE patients. Furthermore, pathogen-induced proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β, markedly and selectively up-regulate pyruvate dehydrogenase 4 (PDK4) and reduce pyruvate dehydrogenase activity and glycolysis, resulting in “energy crisis” in various organs including endothelial cells in the brain of IAE infants.

The peroxisome proliferator-activated receptors (PPARs) play a critical physiological role as lipid sensors and regulators of lipid metabolism by controlling the expression of specific target genes. Among the PPAR agonists, bezafibrate, a hypolipidemic pan-agonist, stimulates CPT2 gene expression and the enzyme activity. In addition, we recently found diisopropylamine dichloroacetate as a repositioning PDK4 inhibitor. I will discuss bezafibrate and diisopropylamine dichloroacetate as potential therapeutic options for “energy crisis” in IAE infants.

Financial support: We thank NIBO, MEXT and Brain Science from the Ministry of Health, Labor and Welfare of Japan.
Keywords: thermolabile CPT II variants; impaired mitochondrial fuel utilization; acylcarnitine ratio; brain edema; carnitine transporter OCTN2; bezafibrate; PDK4 inhibitor.