2. Academic Validation
  3. The inhibitor of glycerol 3-phosphate acyltransferase FSG67 blunts liver regeneration after acetaminophen overdose by altering GSK3β and Wnt/β-catenin signaling

The inhibitor of glycerol 3-phosphate acyltransferase FSG67 blunts liver regeneration after acetaminophen overdose by altering GSK3β and Wnt/β-catenin signaling

  • Food Chem Toxicol. 2019 Mar;125:279-288. doi: 10.1016/j.fct.2019.01.014.
Melissa M Clemens 1,  Stefanie Kennon-McGill 2,  Udayan Apte 3,  Laura P James 4,  Brian N Finck 5,  Mitchell R McGill 6
Affiliations

Affiliations

  • 1 Dept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Interdisciplinary Biomedical Sciences Graduate Program, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 2 Dept. of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 3 Dept. of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
  • 4 Dept. of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 5 Div. of Geriatrics and Nutritional Sciences, Dept. of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • 6 Dept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Dept. of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Center for Dietary Supplement Research, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: mmcgill@uams.edu.
PMID: 30654094 DOI: 10.1016/j.fct.2019.01.014
Abstract

Repair mechanisms after acetaminophen (APAP) hepatotoxicity are poorly understood. We recently discovered that phosphatidic acid (PA) increases in mice and humans after APAP overdose, and is critical for liver regeneration. Here, we hypothesized that PA inhibits glycogen synthase kinase-3β (GSK3β), a component of canonical Wnt/β-catenin signaling, after APAP overdose. To test that, we treated mice with 300 mg/kg APAP at 0 h followed by vehicle or 20 mg/kg of the glycerol 3-phosphate Acyltransferase Inhibitor FSG67 at 3, 24 and 48 h. Some mice also received the GSK3 inhibitor L803-mts. Blood and liver were collected at multiple time points. Consistent with our earlier results, FSG67 did not affect toxicity (ALT, histology), APAP bioactivation (total glutathione), or oxidative stress (oxidized glutathione), but did reduce expression of proliferating cell nuclear antigen (PCNA) at 52 h. We then measured GSK3β phosphorylation and found it was dramatically decreased by FSG67 at 24 h, before PCNA dropped. Expression of cyclin D1, downstream of Wnt/β-catenin, was also reduced. To determine if the effect of FSG67 on GSK3β is important, we treated mice with FSG67 and L803-mts after APAP. Importantly, L803-mts rescued hepatocyte proliferation and survival. Our data indicate PA and lysoPA may support recovery after APAP overdose by inhibiting GSK3β.

Keywords

Biomarkers; Cell growth; Drug-induced liver injury; Lipid metabolism; Lipid signaling; Lipids.

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