Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α

Shailendra Kumar Dhar Dwivedi, Nidhi Singh, Rashmi Kumari, Jay Sharan Mishra, Sarita Tripathi, Priyam Banerjee, Priyanka Shah, Vandana Kukshal, Abdul Malik Tyagi, Anil Nilkanth Gaikwad, Rajnish Kumar Chaturvedi, Durga Prasad Mishra, Arun Kumar Trivedi, Somali Sanyal, Naibedya Chattopadhyay, Ravishankar Ramachandran, Mohammad Imran Siddiqi, Arun Bandyopadhyay, Ashish Arora, Thomas LundåsenSayee Priyadarshini Anakk, David D. Moore, Sabyasachi Sanyal

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptorγ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1α expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1α promoter reporter activity, mRNA, and protein expression. This induction in PGC-1α concomitantly enhances mitochondrial mass and expression of several PGC-1α 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 α (ERRα). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1α mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1α expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differencesrevealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERRα-FXRPGC-1α and small heterodimer partner offers new insights into the biological functions of ERRα and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology.

Original languageEnglish (US)
Pages (from-to)922-932
Number of pages11
JournalMolecular Endocrinology
Volume25
Issue number6
DOIs
StatePublished - Jun 2011
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
Bile Acids and Salts
Estrogen Receptors
Knockout Mice
Co-Repressor Proteins
Messenger RNA
Knowledge Bases
Liver
Estrogens
Skeletal Muscle
Proteins
Homeostasis
GW 4064
Cell Line
Therapeutics
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Dwivedi, S. K. D., Singh, N., Kumari, R., Mishra, J. S., Tripathi, S., Banerjee, P., ... Sanyal, S. (2011). Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α. Molecular Endocrinology, 25(6), 922-932. https://doi.org/10.1210/me.2010-0512

Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α. / Dwivedi, Shailendra Kumar Dhar; 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.

In: Molecular Endocrinology, Vol. 25, No. 6, 06.2011, p. 922-932.

Research output: Contribution to journalArticle

Dwivedi, SKD, Singh, N, Kumari, R, Mishra, JS, Tripathi, S, Banerjee, P, Shah, P, Kukshal, V, Tyagi, AM, Gaikwad, AN, Chaturvedi, RK, Mishra, DP, Trivedi, AK, Sanyal, S, Chattopadhyay, N, Ramachandran, R, Siddiqi, MI, Bandyopadhyay, A, Arora, A, Lundåsen, T, Anakk, SP, Moore, DD & Sanyal, S 2011, 'Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α', Molecular Endocrinology, vol. 25, no. 6, pp. 922-932. https://doi.org/10.1210/me.2010-0512
Dwivedi, Shailendra Kumar Dhar ; 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. / Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α. In: Molecular Endocrinology. 2011 ; Vol. 25, No. 6. pp. 922-932.
@article{2466f67fce174f158334d163fae952c1,
title = "Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α",
abstract = "Peroxisome proliferator-activated receptorγ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1α expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1α promoter reporter activity, mRNA, and protein expression. This induction in PGC-1α concomitantly enhances mitochondrial mass and expression of several PGC-1α 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 α (ERRα). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1α mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1α expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differencesrevealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERRα-FXRPGC-1α and small heterodimer partner offers new insights into the biological functions of ERRα and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology.",
author = "Dwivedi, {Shailendra Kumar Dhar} and Nidhi Singh and Rashmi Kumari and Mishra, {Jay Sharan} and Sarita Tripathi and Priyam Banerjee and Priyanka Shah and Vandana Kukshal and Tyagi, {Abdul Malik} and Gaikwad, {Anil Nilkanth} and Chaturvedi, {Rajnish Kumar} and Mishra, {Durga Prasad} and Trivedi, {Arun Kumar} and Somali Sanyal and Naibedya Chattopadhyay and Ravishankar Ramachandran and Siddiqi, {Mohammad Imran} and Arun Bandyopadhyay and Ashish Arora and Thomas Lund{\aa}sen and Anakk, {Sayee Priyadarshini} and Moore, {David D.} and Sabyasachi Sanyal",
year = "2011",
month = "6",
doi = "10.1210/me.2010-0512",
language = "English (US)",
volume = "25",
pages = "922--932",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "6",

}

TY - JOUR

T1 - Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α

AU - Dwivedi, Shailendra Kumar Dhar

AU - Singh, Nidhi

AU - Kumari, Rashmi

AU - Mishra, Jay Sharan

AU - Tripathi, Sarita

AU - Banerjee, Priyam

AU - Shah, Priyanka

AU - Kukshal, Vandana

AU - Tyagi, Abdul Malik

AU - Gaikwad, Anil Nilkanth

AU - Chaturvedi, Rajnish Kumar

AU - Mishra, Durga Prasad

AU - Trivedi, Arun Kumar

AU - Sanyal, Somali

AU - Chattopadhyay, Naibedya

AU - Ramachandran, Ravishankar

AU - Siddiqi, Mohammad Imran

AU - Bandyopadhyay, Arun

AU - Arora, Ashish

AU - Lundåsen, Thomas

AU - Anakk, Sayee Priyadarshini

AU - Moore, David D.

AU - Sanyal, Sabyasachi

PY - 2011/6

Y1 - 2011/6

N2 - Peroxisome proliferator-activated receptorγ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1α expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1α promoter reporter activity, mRNA, and protein expression. This induction in PGC-1α concomitantly enhances mitochondrial mass and expression of several PGC-1α 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 α (ERRα). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1α mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1α expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differencesrevealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERRα-FXRPGC-1α and small heterodimer partner offers new insights into the biological functions of ERRα and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology.

AB - Peroxisome proliferator-activated receptorγ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1α expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1α promoter reporter activity, mRNA, and protein expression. This induction in PGC-1α concomitantly enhances mitochondrial mass and expression of several PGC-1α 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 α (ERRα). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1α mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1α expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differencesrevealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERRα-FXRPGC-1α and small heterodimer partner offers new insights into the biological functions of ERRα and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology.

UR - http://www.scopus.com/inward/record.url?scp=79957657436&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79957657436&partnerID=8YFLogxK

U2 - 10.1210/me.2010-0512

DO - 10.1210/me.2010-0512

M3 - Article

C2 - 21493670

AN - SCOPUS:79957657436

VL - 25

SP - 922

EP - 932

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 6

ER -