PhD ceremony: J. Woudenberg, 14.45 uur, Academiegebouw, Broerstraat 5, Groningen
Thesis: Novel a spects of peroxisome composition and function in the liver
Promotor(s): prof. A.J. Moshage
Faculty: Medical Sciences
Peroxisomes are organelles that are involved in important liver functions, including bile salt biosynthesis and lipid metabolism. In this thesis we report several novel aspects of peroxisome composition and function in different liver cell types.
We analyzed the function of liver peroxisomes with respect to bile salt homeostasis and liver fibrosis. We obtained proof that unconjugated bile acids transit through hepatocyte peroxisomes to become (re-)conjugated. This implies the presence of putative bile salt transporters in the peroxisomal membrane. Moreover, we show that typical peroxisomal proteins in hepatocytes might be present at different subcellular locations in other liver cell types. In activated hepatic stellate cells (aHSCs), we detected the peroxisomal membrane protein PMP70 in cellular fibers and showed that PMP70 is required for the development of the α -smooth muscle actin network. Therefore, PMP70 might be required for aHSC plasticity and contractility during liver fibrosis.
In addition, we performed a detailed analysis on peroxisomal membrane proteins and their putative association with cholesterol-enriched membrane microdomains (lipid rafts). We observed that caveolin-1, which resides in the plasma membrane in liver endothelial cells and hepatic stellate cells, localizes to the peroxisomal membrane of hepatocytes. This may be important for peroxisomal processes involved in liver regeneration. Finally, we found that hepatocyte peroxisomes contain different subtypes of lipid rafts. At least one of these subtypes is crucial for peroxisome biogenesis.
Taken together, this thesis demonstrates novel functions of peroxisomes in the liver, that may have implications for several liver diseases, in particular liver fibrosis and cholestatic disorders.
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