TARGETING NUCLEAR BILE ACID RECEPTOR FXR IN PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

Progressive Familial Intrahepatic Cholestasis (PFIC) includes 3 diseases caused by mutations in genes responsible for bile formation, characterized by early onset, progressive behavior and severe prognosis: manifested in the first years of life, they often lead to liver failure before adulthood. Clinical presentation combines failure to thrive with pruritus and jaundice. These conditions are cause by mutations in genes responsible for proper bile formation and flow. Homozygous mutations in the “pump” for bile acids located on the hepatocyte plasma membrane facing the biliary canaliculus (bile acid export pump: ATP Binding Cassette (ABC)-B11) is the cause PFIC type 2. PFIC type 3 is caused by mutations in the phospholipid transporter (ABC-B4). While liver transplantation is the only curative therapy at the moment, new hope comes from recent insights into nuclear receptor physiology in the gut-liver axis. Proper bile formation, in fact, relies on the coordinate activity of liver and intestine, and its modulation by dietary and hormonal signals. Nuclear receptors achieve these functions. Nuclear receptors are the gatekeepers of lipid welfare in the body: after activation by specific ligands, nuclear receptor prime the activation of multiple genes (increased transcription) leading to accurate, synchronized and coherent functional responses. In particular, FXR is the bile acid nuclear sensor, orchestrating bile acid homeostasis through liver and intestine (enterohepatic circulation). In the hepatocyte FXR directly up-regulates biliary bile acid and phospholipid secretion. In the enterocyte FXR induces the expression of the hormone Fibroblast Growth Factor (FGF)-15 which inhibits hepatic bile acid synthesis through cholesterol 7a-hydroxylase CYP7A1 suppression. Intestinal FXR activation is mandatory for the inhibition of bile acid synthesis. Since bile acid are cytotoxic-detergent molecules, strategies aiming at reducing bile acid levels are anticipated to be beneficial.