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Bilirubin nanoparticles activate PPARalpha to remodel the hepatic lipidome and produce hepatic ketones in obese mice, improving liver function
Author(s) -
Creeden Justin,
Gordon Darren,
Stec Donald,
Donald Matthew,
Mitchell Zachary,
Morris Andrew,
Stec David,
Hinds Terry
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01992
Subject(s) - bilirubin , medicine , endocrinology , metabolome , fatty liver , liver function , chemistry , disease , metabolite
Global obesity has nearly tripled over the last five decades, leading to comorbidities such as non‐alcoholic fatty liver disease (NAFLD), insulin‐resistant diabetes, and cardiovascular disease. Pharmaceutical interventions remain limited, and many anti‐obesity therapeutics such as sibutramine may be associated with deleterious cardiovascular outcomes. There is an urgent need for new, effective, and safe therapeutic strategies for obesity and comorbidities such as NAFLD. Our previous work has shown that bilirubin functions as a hormone by binding directly to the PPARalpha nuclear receptor to reduce adiposity and NAFLD, which suggests that it might have a potential therapeutic use. However, bilirubin is very hydrophobic, which lowers its translation potential. Bilirubin nanoparticles, a soluble form of bilirubin made by PEGylating bilirubin (PEG‐BR), can be dissolved in saline. We treated diet‐induced obese mice with NAFLD by IP injection with the bilirubin nanoparticles (30 mg/kg every 48 hours) or vehicle for four weeks. We found that bilirubin nanoparticle treatment improved hepatic function in obese mice with NAFLD by lowering AST and ALT, biomarkers of liver dysfunction. Lipidomic analysis of the livers using mass spectrometry showed remodeling of the hepatic lipid profile and significantly reduced (p<0.05) ceramide and dihydroceramide lipid species in obese mice treated with bilirubin nanoparticles. We found that bilirubin nanoparticles activated PPARalpha and ACOX1 to induce fatty acid β‐oxidation. Further analysis of the metabolome using a Bruker In Vitro Diagnostic Research platform with nuclear magnetic resonance spectroscopy showed significantly increased (p<0.05) plasma ketone β‐hydroxybutyrate concentrations in subjects treated with bilirubin nanoparticles. These data suggest that bilirubin nanoparticles activate the PPARalpha‐induced transcriptome to remodel the hepatic lipid profile, increase fatty acid β‐oxidation, and use of these metabolites for the generation of ketones. These data indicate that bilirubin nanoparticles may be used as a potential therapeutic for NAFLD.