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dc.contributor.authorVidimce, Josif
dc.contributor.authorPillay, Johara
dc.contributor.authorShrestha, Nirajan
dc.contributor.authorDong, Lan-feng
dc.contributor.authorNeuzil, Jiri
dc.contributor.authorWagner, Karl-Heinz
dc.contributor.authorHolland, Olivia Jane
dc.contributor.authorBulmer, Andrew Cameron
dc.date.accessioned2021-03-28T23:24:06Z
dc.date.available2021-03-28T23:24:06Z
dc.date.issued2021
dc.identifier.issn1663-9812
dc.identifier.doi10.3389/fphar.2021.586715
dc.identifier.urihttp://hdl.handle.net/10072/403460
dc.description.abstractBackground: Circulating bilirubin is associated with reduced adiposity in human and animal studies. A possible explanation is provided by in vitro data that demonstrates that bilirubin inhibits mitochondrial function and decreases efficient energy production. However, it remains unclear whether hyperbilirubinemic animals have similar perturbed mitochondrial function and whether this is important for regulation of energy homeostasis. Aim: To investigate the impact of unconjugated hyperbilirubinemia on body composition, and mitochondrial function in hepatic tissue and skeletal muscle. Materials and Methods: 1) Food intake and bodyweight gain of 14-week old hyperbilirubinemic Gunn (n = 19) and normobilirubinemic littermate (control; n = 19) rats were measured over a 17-day period. 2) Body composition was determined using dual-energy X-ray absorptiometry and by measuring organ and skeletal muscle masses. 3) Mitochondrial function was assessed using high-resolution respirometry of homogenized liver and intact permeabilized extensor digitorum longus and soleus fibers. 4) Liver tissue was flash frozen for later gene (qPCR), protein (Western Blot and citrate synthase activity) and lipid analysis. Results: Female hyperbilirubinemic rats had significantly reduced fat mass (Gunn: 9.94 ± 5.35 vs. Control: 16.6 ± 6.90 g, p < 0.05) and hepatic triglyceride concentration (Gunn: 2.39 ± 0.92 vs. Control: 4.65 ± 1.67 mg g-1, p < 0.01) compared to normobilirubinemic controls. Furthermore, hyperbilirubinemic rats consumed fewer calories daily (p < 0.01) and were less energetically efficient (Gunn: 8.09 ± 5.75 vs. Control: 14.9 ± 5.10 g bodyweight kcal-1, p < 0.05). Hepatic mitochondria of hyperbilirubinemic rats demonstrated increased flux control ratio (FCR) via complex I and II (CI+II) (Gunn: 0.78 ± 0.16 vs. Control: 0.62 ± 0.09, p < 0.05). Similarly, exogenous addition of 31.3 or 62.5 μM unconjugated bilirubin to control liver homogenates significantly increased CI+II FCR (p < 0.05). Hepatic PGC-1α gene expression was significantly increased in hyperbilirubinemic females while FGF21 and ACOX1 was significantly greater in male hyperbilirubinemic rats (p < 0.05). Finally, hepatic mitochondrial complex IV subunit 1 protein expression was significantly increased in female hyperbilirubinemic rats (p < 0.01). Conclusions: This is the first study to comprehensively assess body composition, fat metabolism, and mitochondrial function in hyperbilirubinemic rats. Our findings show that hyperbilirubinemia is associated with reduced fat mass, and increased hepatic mitochondrial biogenesis, specifically in female animals, suggesting a dual role of elevated bilirubin and reduced UGT1A1 function on adiposity and body composition.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherFrontiers Media SA
dc.relation.ispartofjournalFrontiers in Pharmacology
dc.relation.ispartofvolume12
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3214
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsPharmacology & Pharmacy
dc.subject.keywordslipids
dc.subject.keywordsrespiration
dc.titleMitochondrial Function, Fatty Acid Metabolism, and Body Composition in the Hyperbilirubinemic Gunn Rat
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationVidimce, J; Pillay, J; Shrestha, N; Dong, L-F; Neuzil, J; Wagner, K-H; Holland, OJ; Bulmer, AC, Mitochondrial Function, Fatty Acid Metabolism, and Body Composition in the Hyperbilirubinemic Gunn Rat, Frontiers in Pharmacology, 2021, 12
dcterms.dateAccepted2021-01-11
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/
dc.date.updated2021-03-28T23:17:22Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2021 Vidimce, Pillay, Shrestha, Dong, Neuzil, Wagner, Holland and Bulmer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
gro.hasfulltextFull Text
gro.griffith.authorBulmer, Andrew C.
gro.griffith.authorHolland, Olivia J.
gro.griffith.authorNeuzil, Jiri


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