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

Dhar Dwivedi, Shailendra Kumar and Singh, Nidhi and Mishra, Jay Sharan and Kumari, Rashmi and Tripathi, Sarita and Banerjee, Priyam and Shah, Priyanka 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.

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    Abstract

    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

    Item Type: Article
    URI: http://www.eprints.iicb.res.in/id/eprint/1309
    Subjects: Cell Biology & Physiology
    Divisions: Indian Institute of Chemical Biology
    Depositing User: Ms Sutapa Ganguly
    Date Deposited: 25 Jan 2012 10:46
    Last Modified: 25 Jan 2012 11:27
    Official URL: http://dx.doi.org/10.1210/me.2010-0512
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