PhD ceremony Mr. M.O. Hoeke: The role of vitamin A in bile bile acid synthesis and transport and the relevance for cholestatic liver disease

PhD ceremony: Mr. M.O. Hoeke, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The role of vitamin A in bile bile acid synthesis and transport and the relevance for cholestatic liver disease

Promotor(s): prof. K.N. Faber, prof. H. Moshage

Faculty: Medical Sciences

Absorption of fat-soluble vitamin A depends on bile salts, which are synthesized in the liver and give bile its emulsifying properties. Bile salts are potentially toxic compounds, so their synthesis and transport in the enterohepatic circulation are tightly regulated. Bile acids are ligands for the bile acids sensor FXR (farnesoid X receptor), a ligand activated transcription factor. Via FXR bile acids regulate key genes involved in bile salt synthesis and transport. In order to regulate transcription of its target genes, FXR dimerizes with the retinoid X receptor (RXR). Via RXR vitamin A could influence bile salt homeostasis. Moreover, vitamin A is stored in the liver and liver diseases are often accompanied by vitamin A deficiency (VAD). This demonstrates a network of interactions between bile salts and vitamin A.

The research described in this thesis shows that vitamin A influences expression of FXR target genes and thus bile salt homeostasis. The bile salt export pump (BSEP) in the liver shows maximal expression in the absence of vitamin A, while other FXR-target genes such as SHP (small heterodimer partner) en FGF19 (fibroblast growth factor 19), which both inhibit bile salt synthesis, are maximally expressed in the presence of vitamin A. VAD alone increased plasma bile salt concentrations in rats. The other way around, cholestasis is often accompanied by VAD and these results suggest that VAD might contribute to a cholestatic phenotype. Therefore, we studied the effect of VAD in an animal model of obstructive cholestasis. VAD dramatically aggravated the clinical symptoms, while vitamin A therapy normalized the clinical symptoms in vitamin A deficient rats.

These results show that vitamin A is an important co-regulator of bile salt homeostasis and urge the close monitoring of vitamin A levels in cholestatic patients, as vitamin A shortage could rapidly deteriorate the patient’s condition.