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 Hosick, Lucien McBeth, Andrea Nestor-Kalinoski, Heather A. Drummond, Abdulhadi A. Alamodi, Michael W. Hankins, John P. Vanden Heuvel, David E. Stec

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23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)25179-25191
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number48
DOIs
StatePublished - 25 Nov 2016

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biliverdin reductase
Glycogen Synthase Kinase 3
Peroxisome Proliferator-Activated Receptors
Phosphorylation
Liver
Serine
Biliverdine
Glycogen Synthase Kinases
Proteins
Ubiquitination
Liver Failure
Fatty Liver
Glycogen
Lipid Metabolism
Bilirubin
Liver Cirrhosis
Liver Diseases
Transcription Factors
Phosphotransferases
Insulin

Cite this

Hinds, Terry D. ; Burns, Katherine A. ; Hosick, Peter ; McBeth, Lucien ; Nestor-Kalinoski, Andrea ; Drummond, Heather A. ; Alamodi, Abdulhadi A. ; Hankins, Michael W. ; Vanden Heuvel, John P. ; Stec, David E. / 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. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 48. pp. 25179-25191.
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title = "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",
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.",
author = "Hinds, {Terry D.} and Burns, {Katherine A.} and Peter Hosick and Lucien McBeth and Andrea Nestor-Kalinoski and Drummond, {Heather A.} and Alamodi, {Abdulhadi A.} and Hankins, {Michael W.} and {Vanden Heuvel}, {John P.} and Stec, {David E.}",
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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. / Hinds, Terry D.; Burns, Katherine A.; Hosick, Peter; McBeth, Lucien; Nestor-Kalinoski, Andrea; Drummond, Heather A.; Alamodi, Abdulhadi A.; Hankins, Michael W.; Vanden Heuvel, John P.; Stec, David E.

In: Journal of Biological Chemistry, Vol. 291, No. 48, 25.11.2016, p. 25179-25191.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - 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

AU - Hinds, Terry D.

AU - Burns, Katherine A.

AU - Hosick, Peter

AU - McBeth, Lucien

AU - Nestor-Kalinoski, Andrea

AU - Drummond, Heather A.

AU - Alamodi, Abdulhadi A.

AU - Hankins, Michael W.

AU - Vanden Heuvel, John P.

AU - Stec, David E.

PY - 2016/11/25

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N2 - 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.

AB - 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.

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JO - Journal of Biological Chemistry

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SN - 0021-9258

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