title: Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α.
abstract: Peroxisome proliferator-activated receptor γ 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 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 ERRα-FXR-PGC-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.
authors.affiliation: Endocrinology Division, Institute of Toxicological Research, Council of Scientific and Industrial Research, Lucknow 226001, India.
authors.forename: Shailendra Kumar Dhar
authors.initials: SK
authors.lastname: Dwivedi
authors.forename: Nidhi
authors.initials: N
authors.lastname: Singh
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kumari
authors.forename: Jay Sharan
authors.initials: JS
authors.lastname: Mishra
authors.forename: Sarita
authors.initials: S
authors.lastname: Tripathi
authors.forename: Priyam
authors.initials: P
authors.lastname: Banerjee
authors.forename: Priyanka
authors.initials: P
authors.lastname: Shah
authors.forename: Vandana
authors.initials: V
authors.lastname: Kukshal
authors.forename: Abdul Malik
authors.initials: AM
authors.lastname: Tyagi
authors.forename: Anil Nilkanth
authors.initials: AN
authors.lastname: Gaikwad
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Chaturvedi
authors.forename: Durga Prasad
authors.initials: DP
authors.lastname: Mishra
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Trivedi
authors.forename: Somali
authors.initials: S
authors.lastname: Sanyal
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
authors.forename: Ravishankar
authors.initials: R
authors.lastname: Ramachandran
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.forename: Arun
authors.initials: A
authors.lastname: Bandyopadhyay
authors.forename: Ashish
authors.initials: A
authors.lastname: Arora
authors.forename: Thomas
authors.initials: T
authors.lastname: Lundåsen
authors.forename: Sayee Priyadarshini
authors.initials: SP
authors.lastname: Anakk
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D017930:Genes, Reporter; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D000097983:ERRalpha Estrogen-Related Receptor; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D007555:Isoxazoles; D008156:Luciferases; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; D000099150:Receptor, Farnesoid X-Activated; C485290:Ppargc1a protein, mouse; C099713:nuclear receptor subfamily 0, group B, member 2; C412815:GW 4064