Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3β Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) α

Terry D Hinds,Katherine A Burns,Peter A Hosick,Lucien Mcbeth,Andrea Nestor-Kalinoski,Heather A Drummond,Abdulhadi A Alamodi,Michael W Hankins,John P Vanden Heuvel,David E Stec

doi:10.1074/jbc.m116.731703

Abstract

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 3β (GSK3β) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3β phosphorylates serine 73 (Ser(P)73) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3β activity and Ser(P)73 of PPARα, which resulted in decreased PPARα 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-GSKβ-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease.

Highlights

Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, resulting in liver cirrhosis and failure
After LBVRA-KO mice were placed on a high fat diet, no differences in body weight, body composition, or plasma bilirubin levels were observed between the LBVRA-KO and flox control mice (Fig. 1, E–G)
These results suggest that a liver-specific loss of Biliverdin reductase A (BVRA) promotes hepatic insulin resistance that, in turn, leads to increased plasma glucose and insulin levels, which most likely stemmed from reduced insulin signaling and not insulin receptor expression

Summary

Edited by Joel Gottesfeld

Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, resulting in liver cirrhosis and failure. The liverspecific 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-GSK␤-PPAR␣ axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease. We recently showed that BVRA-derived bilirubin IX␣ binds directly to the nuclear receptor transcription factor PPAR␣ to reduce adiposity and blood glucose [8]. This is the first known ligand function reported for bilirubin. PPAR␣ in the regulation of hepatic lipid metabolism and opens new avenues for therapeutic targeting

Results

Discussion

Experimental Procedures