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Bile Acid Receptor Agonist GW4064 Regulates PPAR� Coactivator-1� Expression Through Estrogen Receptor-Related Receptor �

IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata

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Title Bile Acid Receptor Agonist GW4064 Regulates PPAR� Coactivator-1� Expression Through Estrogen Receptor-Related Receptor �
 
Creator Dhar Dwivedi, Shailendra Kumar
Singh, Nidhi
Kumari, Rashmi
Mishra, Jay Sharan
Tripathi, Sarita
Banerjee, Priyam
Shah, Priyanka
Kukshal, Vandana
Tyagi, Abdul Malik
Gaikwad, Anil Nilkanth
Chaturvedi, Rajnish Kumar
Mishra, Durga Prasad
Trivedi, Arun Kumar
Sanyal, Somali
Chattopadhyay, Naibedya
Ramachandran, Ravishankar
Siddiqi, Mohammad Imran
Bandyopadhyay, Arun
Arora, Ashish
Lundåsen, Thomas
Anakk, Sayee Priyadarshini
Moore, David D
Sanyal, Sabyasachi
 
Subject Cell Biology & Physiology
 
Description Peroxisome proliferator-activated receptor� coactivator-1� (PGC-1�) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1� an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1� expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1� promoter reporter activity, mRNA, and protein expression. This induction in PGC-1� concomitantly enhances mitochondrial mass and expression of several PGC-1� target genes involved in mitochondrial function. Using FXR-rich or FXR-nonexpressing cell lines and tissues, we found that this effect of GW4064 is not mediated directly by FXR but occurs via activation of estrogen receptor-related receptor � (ERR�). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1� mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1� expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differences revealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERR�-FXRPGC- 1� and small heterodimer partner offers new insights into the biological functions of ERR� and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology. (Molecular Endocrinology 25: 922–932, 2011)
 
Publisher Endocrine Society
 
Date 2011
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/262/1/MOLECULAR_ENDOCRINOLOGY%2C25(6)%2C_922%2D932%2C2011[45].pdf
Dhar Dwivedi, Shailendra Kumar and Singh, Nidhi and Kumari, Rashmi and Mishra, Jay Sharan and Tripathi, Sarita and Banerjee, Priyam and Shah, Priyanka and Kukshal, Vandana and Tyagi, Abdul Malik and Gaikwad, Anil Nilkanth and Chaturvedi, Rajnish Kumar and Mishra, Durga Prasad and Trivedi, Arun Kumar and Sanyal, Somali and Chattopadhyay, Naibedya and Ramachandran, Ravishankar and Siddiqi, Mohammad Imran and Bandyopadhyay, Arun and Arora, Ashish and Lundåsen, Thomas and Anakk, Sayee Priyadarshini and Moore, David D and Sanyal, Sabyasachi (2011) Bile Acid Receptor Agonist GW4064 Regulates PPAR� Coactivator-1� Expression Through Estrogen Receptor-Related Receptor �. Molecular Endocrinology, 25 (6). pp. 922-932.
 
Relation http://dx.doi.org/10.1210/me.2010-0512
http://www.eprints.iicb.res.in/262/