The functional relationship between peroxisomes, bile salts and lipid rafts in the liver

PhD ceremony: Mr. K.P. Rembacz, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The functional relationship between peroxisomes, bile salts and lipid rafts in the liver

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

Faculty: Medical Sciences

The liver produces bile that solubilizes fatty compounds so that dietary fats can be absorbed in the intestinal tract and toxins and waste products are excreted with the faeces. The functional compounds in bile are bile acids. They are synthesized in the liver and after performing their function in the small intestine are absorbed in the terminal ileum and transported via the blood back to the liver. Bile acids may shuttle over 20 times between the liver and the ileum, before they escape intestinal absorption and are lost in the faeces. Liver and intestinal cells contain specific proteins in their cellular membranes that are responsible for the unidirectional transport of bile acids. Impaired bile acid transport leads to liver damage. Intestinal bacteria modify bile acids, e.g., remove their amino acid (glycine or taurine) side chain, which has to be corrected in the liver.

In this thesis we show that this reconjugation of bile acids with glycine or taurine takes place in a small organelle in liver cells, the peroxisomes. This implies that bile acid transport between liver and intestine also includes shuttling in and out peroxisomes in liver cells and is crucial to maintain functional bile. We show that a peroxisomal membrane protein, PMP70, is required for efficient bile acid reconjugation and transport, and that PMP70 exists in cholesterol-containing lipid microdomains, like other bile acid transporters. Peroxisomal lipid rafts were not detected in human peroxisomes before, but we found that they are essential for the formation of this organelle.