Academisch Medisch Centrum Universiteit van Amsterdam

Cholestatic liver disease

    Pediatric cholestasis

    Primary Sclerosing Cholangitis

Non-alcoholic fatty liver

    NASH

    Role of bile acids in NAFL/NASH

Basic Research

    Regulatory roles of fibroblast growth factors in metabolism

    Fibroblast growth factor receptors

Clinical Studies on viral hepatitis

    Hepatitis B

    Hepatitis C

Recent studies show strong indications for bile acids having signaling roles in metabolism. Relevant bile acid receptors include the farnesoid X-receptor FXR, and the G-protein membrane coupled bile acid receptor, TGR5. FXR is a member of the nuclear hormone receptor family located in e.g. liver and intestine .
In the liver FXR stimulates the expression of a number of ABC transmembrane transporters, including the canalicular bile acid export pump BSEP, and SHP, an important regulatory protein that blocks the expression of CYP7A1, the rate determining enzyme in the transfer of cholesterol to bile acids. In the intestine FXR acts as a transcriptional regulator of FGF19. FGF19 is a member of the fibroblast growth factor family with a metabolic function. FGF19 is secreted into the portal circulation and in the liver binds to its receptor FGFR4. Activation of FGFR4 leads to a reduction of CYP7A1 expression in a mechanism that overrules that action of SHP. This makes FGF19 the strongest regulator of de novo bile acid synthesis in the liver and it is interesting to note that this regulating protein is produced in the intestine thus showing a strong interaction between intestine and liver. This is even more striking if one realizes that FGF19 also regulates lipid and carbohydrate metabolism in the liver.
Currently we study the action of FGF19 in patients with a non-alcoholic fatty liver. Preliminary evidence indicated that in patients with NAFL and insulin resistance there is a degree of resistance to the actions of FGF19 in the liver contributing to the unrelenting accumulation of fat in the liver.
The other bile acid receptor TGR5, is located in the intestine, bile ducts, brown adipose tissue and brain. TGR5 has a major regulatory role in metabolism. In brown adipose tissue it stimulates the conversion of inactive thyroid hormone T4 to active T3, thus stimulating energy metabolism. In the intestine binding of TGR5 by bile acids stimulates the synthesis of glucagon-like peptide 1 GLP1, that affects the secretion of insulin by the pancreas. These results show that bile acids may have a much more central place in metabolism than hitherto realized.