Bile Acid Receptor Agonist GW4064 Regulates PPARγ Coactivator-1α Expression Through Estrogen Receptor-Related Receptor α

Peroxisome proliferator-activated receptor alpha coactivator-1 alpha (PGC-1 alpha) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1 alpha an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1 alpha expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1 alpha promoter reporter activity, mRNA, and protein expression. This induction in PGC-1 alpha concomitantly enhances mitochondrial mass and expression of several PGC-1 alpha 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 alpha (ERR alpha). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1 alpha mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1 alpha 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 alpha-FXR-PGC-1 alpha and small heterodimer partner offers new insights into the biological functions of ERR alpha and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology. (Molecular Endocrinology 25: 922-932, 2011)