Estrogen-related receptor (ERR) plays critical roles in the transcriptional regulation of genes
involved in mitochondrial bioenergetics, TCA cycle, mitochondrial oxidative phosphorylation, and
fatty acid ß-oxidation. This project intends to discover the roles of ERR as novel transcriptional
factor for lipid metabolism its involvement in lipid pathology development in the liver. To address
the function of ERR in dyslipidemia, we developed a novel small molecule inhibitor (ERR-PA) that
can block the binding of ERRs to the promoters of its target genes. Using this compound in diet
and genetic models of liver steatosis (NAFLD/ALD) and steatohepatitis (NASH/ASH), our
preliminary studies showed that inhibiting ERR robustly blocks the development of steatosis and
reverses the lipid accumulation in models where liver steatosis is induced by diet and ethanol
feeding as well as genetic alterations. ERR-PA also significantly reduced the fibrosis and
inflammation occurring in established steatohepatitis. Using these in vivo as well as in vitro
systems, we will explore the molecular mechanisms by which ERR inhibition suppresses the
progression of liver disease. The hypothesis to be tested is that ERRs positively regulate
transcription of genes encoding enzymes for anabolic lipid metabolism and inhibiting this action
blocks steatosis and associated inflammation and fibrosis in NASH/ASH. We will address this
hypothesis with the following three aims. Aim1 will investigate the regulation of lipid metabolism
via the transcriptional activity of ERRs. This aim will explore the transcriptional complex by which
ERRa regulates de novo lipogenesis, glycerolipid biosynthesis and fatty acid ß-oxidation. Aim2
will explore the regulation of ERRs by insulin signaling based on our previous discover that ERRa
is a downstream target of insulin/PI3K/AKT signaling signal regulated via AKT phosphorylation
on CREB and upregulation of PGC-1a. Aim3 will determine the effect of ERR inhibition on
oxidative lipid damage in during ASH/NASH development. This aim will investigate lipid, oxidized
lipid and other derivatives, ROS production and their contribution to liver damage. The proposed
project will explore ERRa as a potential target for inhibiting and reversing fatty liver diseases. The
mechanistic and translations approaches will uncover novel biology for lipid metabolism as well
as test the therapeutic effect of a small molecule polyamide.