Project Details
Description
ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most prevalent chronic liver diseases in the
world, with non-alcoholic steatohepatitis (NASH) being an extreme form of NAFLD. Our team proposes to
investigate the novel concept that intestine-selective FXR antagonism has the potential to prevent or reverse
NAFLD/NASH. FXR is the major bile acid sensor in the body and serves to mediate the dialog between the liver
and small intestine regarding bile acid levels, bile acid synthesis, transport, and enterohepatic circulation, and
also regulates lipid and glucose levels in the liver. As such, FXR was identified in human trials as a promising
target for the prevention and/or amelioration of many metabolic diseases, including NAFLD/NASH. We have
recently established intestinal FXR as a major regulator of diet-induced obesity and NAFLD, particularly through
antagonism of the receptor with the conjugated bile acid tauro-β-muricholic acid (TβMCA). We reported that
tempol, a potent antioxidant, inhibited the FXR signaling pathway, due to accumulation of intestinal TβMCA, an
antagonist of FXR, resulting from reduced activity of the Lactobacillus-associated bile salt hydroxylase enzyme.
We further developed glycine-β-muricholic acid (GlyβMCA), a potent, intestine-selective FXR antagonist that
similarly prevents or reversed NAFLD in diet-induced NAFLD models or genetic models, suggesting intestinal
FXR as a promising therapeutic target for NAFLD. These observations have led to the novel central hypothesis:
Antagonism of intestinal FXR prevents the development of NAFLD
In this proposal we plan to address two fundamental gaps in knowledge with respect to FXR antagonism and
NAFLD. First, we will identify using a combination of in vitro and in vivo approaches what chemical features
define an FXR antagonist and develop a better understanding for how these modifications influence the
absorption, distribution, metabolism, and excretion (ADME) of the antagonist and its pharmacodynamic
properties. Second, through the innovative use of cutting-edge techniques—including 16S rRNA gene
sequencing, metagenomics, metatranscriptomics, and metabolomics—and unique mouse models, we plan to
identify how FXR signaling and the gut microbiota are linked in NAFLD pathogenesis. This combination of
approaches will allow us to identify new therapeutic FXR antagonists and to accurately assess how these
compounds influence downstream FXR signaling pathways with the ultimate goal of developing new NAFLD
therapies.
Status | Finished |
---|---|
Effective start/end date | 9/23/19 → 5/31/24 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $368,652.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $368,652.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $368,652.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $24,369.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $352,669.00
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