Mutation in bile acid receptor identified!

Mutation in bile acid receptor identified!
Bile acids are detergents that are produced in the liver and released into the gut to facilitate and promote absorption of lipid nutrients. They are reabsorbed in the gut along with the nutrients and returned to the liver via the portal vein. Excessive bile acid levels are toxic, and both their hepatic production and enterohepatic circulation are stringently regulated.

Bile acid levels are sensed by a nuclear bile acid receptor termed the farnesoid X receptor (FXR), encoded by the NR1H4 gene. Elevated bile acid levels activate FXR to induce a program that represses hepatocyte bile acid biosynthesis and uptake while increasing export.
This suppression of bile acid production makes FXR a therapeutic target for cholestatic liver disease, and clinical trials of FXR agonists in primary biliary cirrhosis are promising. Initial clinical results indicate that FXR agonists may have beneficial effects in non-alcoholic fatty liver disease and the metabolic syndrome. Thus, FXR is both a key modulator of multiple metabolic and hepatocyte-protective pathways and an emerging therapeutic target for both cholestatic and metabolic diseases.
Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Researchers report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism.
Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression.
These findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.