Premium
Liver specific knockout of biliverdin reductase‐A (BVRA) enhances high fat diet induced hepatic steatosis and type II diabetes in mice
Author(s) -
Alamodi Abdulhadi,
Hosick Peter,
Drummond Heather,
Hinds Terry,
Stec David
Publication year - 2015
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.29.1_supplement.1004.6
Subject(s) - medicine , steatosis , endocrinology , biliverdin reductase , bilirubin , albumin , hepatocyte , chemistry , knockout mouse , western blot , oil red o , biliverdin , biology , enzyme , biochemistry , heme , heme oxygenase , receptor , in vitro , adipose tissue , gene , adipogenesis
Biliverdin reductase‐A (BVRA) is the enzyme responsible for the reduction of biliverdin to bilirubin. In order to determine the role of intracellular heptatic bilirubin generation in the development of dietary induced hepatic steatosis, we developed mice with hepatocyte specific deletion of BVRA. Floxed BVRA mice were crossed with mice specifically expressing the Cre recombinase in hepatocytes under the control of the albumin promoter (Alb‐Cre). Liver specific BVRA knockout (KO) mice exhibited a significant decrease in hepatic BVRA protein measured by both Western blot and immunofluorescence. Liver BVRA KO mice also exhibited a significant decrease in hepatic BVR activity as compared to WT mice (4 + 1 vs. 14 + 3 µmoles bilirubin/min/mg protein, P<0.05). Mice were placed on a high fat (60%) diet at 6 weeks of age for 12 weeks. At the end of the 12 week period, liver specific BVRA knockout (KO) mice exhibited significantly greater levels of fat in the liver as compared to control mice measured by echoMRI (21 + 2 vs. 10 + 3 %, P<0.05). A similar increase in hepatic steatosis in the liver of BVRA KO mice was also determined by Oil Red O staining of liver sections (50 + 3 vs. 22 + 5 %, P<0.05). Liver BVRA KO mice also exhibited higher fasting blood glucose levels at the end of the 12 week study as compared to control mice (155 + 3 vs. 120 + 2 mg/dL, P<0.05). These results suggest that intracellular BVRA generation of bilirubin is an important factor to protect the liver against hepatic steatosis and the development of type II diabetes in response to a high fat diet.