Identification and detailed characterization of novel regulators of cellular cholesterol metabolism

Cholesterol is a structural component of cell membranes in higher eukaryotes. It is involved in essential cellular processes like transmembrane signaling and regulation of membrane fluidity. Deregulation of cholesterol metabolism has been implicated in human diseases, such as familial hypercholesterolemia and atherosclerosis. One of the most important coordinators of cholesterol homeostasis is the sterol regulatory element-binding protein (SREBP) family of transcription factors. To date more than 40 SREBP-responsive genes involved in uptake and synthesis of cholesterol have been described. However, our knowledge about this complex network is far from complete.

Performing combined approaches of genome-wide gene expression analyses, cell-based high-throughput RNAi screenings as well as an in silico promoter scan, we identified novel genes highly likely to be involved in cellular cholesterol metabolism. Knocking down one of the most promising candidates (C17orf59), we showed a reduced uptake of DiI-LDL - and therefore cholesterol - into the cell, as well as a scattering of the golgi apparatus. Furthermore, localization studies revealed a large overlap with Lamp1, a marker protein for lysosomes. This suggests a function of our candidate in the endo-/lysosomal system, which plays a key role in cholesterol uptake and distribution.

In summary, our results strongly suggest that C17orf59 has an important role in cholesterol metabolism and thereby confirm our screening results.