Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

  1. Rabina Mainali
  2. Manal Zabalawi
  3. David Long
  4. Nancy Buechler
  5. Ellen Quillen
  6. Chia-Chi Key
  7. Xuewei Zhu
  8. John S Parks
  9. Cristina Furdui
  10. Peter W Stacpoole
  11. Jennifer Martinez
  12. Charles E McCall  Is a corresponding author
  13. Matthew A Quinn  Is a corresponding author
  1. Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, United States
  2. Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, United States
  3. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, United States
  4. Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, United States
5 figures and 4 additional files

Figures

Sepsis Impairs hepatic mitochondrial metabolism.

(A) Top five canonical pathways subject to transcriptional alterations in the liver identified by ingenuity pathway analysis of RNA-seq of sham versus CLP mice (n = 4 mice per group). Blue …

Figure 2 with 1 supplement
Impaired hepatic redox balance in septic mice.

(A) GSEA of the ROS metabolic pathway (GO:0072593) from RNA-seq from livers comparing sham to CLP showing a positive enrichment score (NES = 1.117) (n = 4 mice per group). (B–F) Relative metabolite …

Figure 2—figure supplement 1
Hepatic homocysteine levels in sham and CLP mice.

Ultrahigh-performance liquid chromatography–tandem mass spectroscopy measurement of homocysteine from isolated hepatocytes 30 hr post-surgery. n = 5 sham, n = 8 CLP.

Figure 3 with 1 supplement
Sepsis promotes hepatic steatosis.

(A) Top five induced and repressed physiological pathways in the liver of sham versus CLP mice identified by IPA of RNA-seq. (B) GSEA of the fatty acid metabolic pathway (GO:0019395) from RNA-seq …

Figure 3—figure supplement 1
Fatty acid oxidation and biosynthetic pathways in septic livers.

(A) Heatmap representation of average log2 fold change of genes involved in fatty acid oxidation (GO:0019395) and fatty acid biosynthetic process (GO:0006633) in CLP versus sham operated mice (n = 5 …

Figure 4 with 3 supplements
Sepsis reprograms the hepatic lipidome.

(A) Volcano plot of significantly altered lipids from sham and CLP hepatocytes measured by UPLC–MS/MS (n = 5 sham; n = 8 CLP). (B) Pie chart of lipid compositions from sham and CLP mice. (C) …

Figure 4—figure supplement 1
Hepatic ceramide levels in sham and CLP mice.

Ultrahigh-performance liquid chromatography–tandem mass spectroscopy measurement of (A) dihydroceramide, (B) ceramide, (C) hexosylceramide, and (D) lactosylceramide from isolated hepatocytes 30 hr …

Figure 4—figure supplement 2
Phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin quantifications.

Ultrahigh-performance liquid chromatography–tandem mass spectroscopy measurement of (A) free fatty acid species, (B) phosphatidylcholine species, (C) phosphatidylethanolamine species, and (D) …

Figure 4—figure supplement 3
PI, LPE, and CE levels in septic livers.

Ultrahigh-performance liquid chromatography–tandem mass spectroscopy measurement of (A) phosphatidylinositol, (B) lysophosphatidylethanolamine species, and (C) cholesterol ester from isolated …

PDK inhibition restores hepatic metabolism in septic mice.

(A) Venn diagram of differentially expressed genes (DEGs) assessed by RNA-seq in CLP versus sham compared to CLP+DCA versus sham 30 hr post-surgery (left). Heatmap of average log2 fold change of …

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