COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Figure 9

The effects of increased R-BHB levels on the activity of the transcription factors FOXO3a, FOXO1, HIF1-α, Nrf2, and PGC-1α. (a) DNA wrapped around histones with deacetylated lysines blocks the access of transcription factors, so HDAC function represses transcription. (b) R-BHB, by inhibiting class I HDACs, allows increased histone acetylation, relaxed chromatin, and FOXO3a expression. (c) Chromatin is also relaxed by β-hydroxybutyrylation at promoters such as that of FOXO1 to increase transcription. (d) HIF-1α is activated by RNS. Peroxynitrite S-nitrosylates HIF-1α to inhibit its von Hippel-Landau factor-induced ubiquitination and proteasomal degradation. This stabilizes HIF-1α leading to increased PDK1 expression. This stabilization is likely inhibited by R-BHB, which increases NADPH to decrease ROS/RNS levels. (e) Nrf2 is activated by oxidized DJ-1, and this is regulated by the redox potential of NADP⁺/NADPH that controls the cellular antioxidant potential. The DJ-1 chaperone protein, which is activated by moderate levels of hydrogen peroxide, stimulates the release of Nrf2 from KEAP1 allowing Nrf2 to enter the nucleus and induce antioxidant response element gene expression. (f) PGC-1α is the master regulator of mitochondrial biogenesis. It is a coactivator of ERR-α, FOXO1, FOXO3a, PPARs, and nuclear respiratory factor 1 (NRF1). Abbreviations: Ac: acetate; ARE: antioxidant response element; CA9: carbonic anhydrase 9; CCR7: C-C chemokine receptor type 7; ERR-α: estrogen-related receptor alpha; ETC: electron transport chain; K: lysine; HDAC: histone deacetylase; FIH-1: factor inhibiting HIF-1; FOXO1: forkhead box O1; FOXO3: forkhead box O3; FOXP3: forkhead box P3; G6PC: glucose-6-phosphatase; G6PDH: glucose 6-phosphate dehydrogenase; γGCLM: glutamate cysteine ligase modifier subunit; Glut1: glucose transporter 1; GSRX: glutathione reductase; HIF-1α and HIF-1β: hypoxia-inducible factor 1 alpha and beta; HRE: hypoxia response element; IFNG: interferon gamma gene; IL7R: interleukin-7 receptor; iNOS: inducible nitric oxide synthase; IRF7: interferon regulatory factor 7; KEAP1: Kelch-like ECH-associated protein 1; MAF: musculoaponeurotic fibrosarcoma; Nrf1: nuclear respiratory factor 1; Nrf2: nuclear factor erythroid 2-related factor 2 (NFE2L2); RAG1 and RAG2: recombination activating genes 1 and 2; ONOO^-: peroxynitrite; ONOOH: peroxynitrous acid; P300/CBP: binding protein 300/CREB-binding protein; PDK1 and PDK4: pyruvate dehydrogenase kinases 1 and 4; PGC1-α: PPARG coactivator 1 alpha; PHD2: prolyl-hydroxylase domain protein 2; pVHL: von Hippel-Landau tumor suppressor protein; SCOT/OXCT1: succinyl-CoA-3-oxaloacid CoA transferase also known as 3-oxoacid CoA-transferase 1; SELL: selectin L; SOD2: superoxide dismutase 2; Ub: ubiquitin; VEGF: vascular endothelial growth factor.

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