Bilirubin deficiency renders mice susceptible to hepatic steatosis in the absence of insulin resistance.
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Authors
Chen, Weiyu
Tumanov, Sergey
Fazakerley, Daniel J
Cantley, James
James, David E
Dunn, Louise L
Shaik, Taqi
Suarna, Cacang
Stocker, Roland
Publication Date
2021-11Journal Title
Redox Biol
ISSN
2213-2317
Publisher
Elsevier BV
Volume
47
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Chen, W., Tumanov, S., Fazakerley, D. J., Cantley, J., James, D. E., Dunn, L. L., Shaik, T., et al. (2021). Bilirubin deficiency renders mice susceptible to hepatic steatosis in the absence of insulin resistance.. Redox Biol, 47 https://doi.org/10.1016/j.redox.2021.102152
Abstract
BACKGROUND & AIMS: Plasma concentrations of bilirubin, a product of heme catabolism formed by biliverdin reductase A (BVRA), inversely associate with the risk of metabolic diseases including hepatic steatosis and diabetes mellitus in humans. Bilirubin has antioxidant and anti-inflammatory activities and may also regulate insulin signaling and peroxisome proliferator-activated receptor alpha (PPARα) activity. However, a causal link between bilirubin and metabolic diseases remains to be established. Here, we used the global Bvra gene knockout (Bvra-/-) mouse as a model of deficiency in bilirubin to assess its role in metabolic diseases. APPROACH & RESULTS: We fed mice fat-rich diets to induce hepatic steatosis and insulin resistance. Bile pigments were measured by LC-MS/MS, and hepatic lipids by LC-MS/MS (non-targeted lipidomics), HPLC-UV and Oil-Red-O staining. Oxidative stress was evaluated measuring F2-isoprostanes by GC-MS. Glucose metabolism and insulin sensitivity were verified by glucose and insulin tolerance tests, ex vivo and in vivo glucose uptake, and Western blotting for insulin signaling. Compared with wild type littermates, Bvra-/- mice contained negligible bilirubin in plasma and liver, and they had comparable glucose metabolism and insulin sensitivity. However, Bvra-/- mice exhibited an inflamed and fatty liver phenotype, accompanied by hepatic accumulation of oxidized triacylglycerols and F2-isoprostanes, in association with depletion of α-tocopherol. α-Tocopherol supplementation reversed the hepatic phenotype and observed biochemical changes in Bvra-/- mice. CONCLUSIONS: Our data suggests that BVRA deficiency renders mice susceptible to oxidative stress-induced hepatic steatosis in the absence of insulin resistance.
Keywords
Bilirubin, F(2)-isoprostanes, Insulin signaling, Lipid oxidation, Vitamin E, Animals, Bilirubin, Chromatography, Liquid, F2-Isoprostanes, Fatty Liver, Insulin, Insulin Resistance, Liver, Mice, Mice, Inbred C57BL, Mice, Knockout, Tandem Mass Spectrometry
Identifiers
PMC8498001, 34610553
External DOI: https://doi.org/10.1016/j.redox.2021.102152
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330395
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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