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

Weiyu Chen, Sergey Tumanov, Daniel Fazarkeley, James Cantley, David E. James, Louise L. Dunn, Taqi Shaik, Cacang Suarna, Roland Stocker

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)
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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.

Original languageEnglish
Article number102152
Number of pages13
JournalRedox Biology
Volume47
Early online date27 Sep 2021
DOIs
Publication statusPublished - Nov 2021

Keywords

  • Bilirubin
  • F-isoprostanes
  • Insulin signaling
  • Lipid oxidation
  • Vitamin E

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