| First Author | Hinds TD Jr | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 48 | Pages | 25179-25191 |
| PubMed ID | 27738106 | Mgi Jnum | J:237631 |
| Mgi Id | MGI:5816394 | Doi | 10.1074/jbc.M116.731703 |
| Citation | Hinds TD Jr, et al. (2016) Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3beta Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) alpha. J Biol Chem 291(48):25179-25191 |
| abstractText | Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3beta (GSK3beta) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3beta phosphorylates serine 73 (Ser(P)73) of the peroxisome proliferator-activated receptor alpha (PPARalpha), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3beta activity and Ser(P)73 of PPARalpha, which resulted in decreased PPARalpha protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKbeta-PPARalpha axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease. |
