Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction
- Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, United States
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, United States
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, United States
- Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, United States
Figures
Figure 1
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 …
Figure 5
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 …
Additional files
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Source data 1
Lipidomic analysis.
- https://cdn.elifesciences.org/articles/64611/elife-64611-data1-v2.xlsx
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Source data 2
Metabolomic analysis.
- https://cdn.elifesciences.org/articles/64611/elife-64611-data2-v2.xlsx
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Source data 3
Transcriptomic analysis.
- https://cdn.elifesciences.org/articles/64611/elife-64611-data3-v2.xlsx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/64611/elife-64611-transrepform-v2.docx
