Bilirubin deficiency renders mice susceptible to hepatic steatosis in the absence of insulin resistance

Chen, Weiyu and Tumanov, Sergey and Fazakerley, Daniel J. and Cantley, James and James, David E. and Dunn, Louise L. and Shaik, Taqi and Suarna, Cacang and Stocker, Roland (2021) Bilirubin deficiency renders mice susceptible to hepatic steatosis in the absence of insulin resistance. Redox Biology, 47. p. 102152. ISSN 22132317

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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 (PPARalpha) 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 alpha-tocopherol. alpha-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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 10 Dec 2021 03:36
Last Modified: 10 Dec 2021 03:36

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