In cells is a busy cargo traffic: The continuous import and export of molecules and their sales within the cell are essential for all vital functions. In the liver, transport and metabolism of LDL-cholesterol are important for regulation of cholesterol level in blood. "Defects in cholesterol metabolism lead to nonalcoholic fatty liver disease (NAFLD), which is characterized by an increased fat storage in the liver - the so-called fatty liver - and increases the risk of dying from liver or cardiovascular disease," says Dr. Christian Grimm from the chair of pharmacology in natural sciences (Head Professor Martin Biel), who is now able to show in animal experiments that the loss of certain cation channels makes them particularly vulnerable to NAFLD.
Cholesterol diet for a new mouse model
As numerous other macromolecules LDL cholesterol is passed through the so-called endolysosomal system into the cell and metabolized: Special vesicles, endosomes, import the LDL-cholesterol in the cell. There they merge with lysosomes, where the LDL cholesterol is broken down by the help of digestive enzymes. "Although the basic operations of the cholesterol metabolism have been studied will, it is still largely unknown which molecules regulate the LDL transport and fusion processes in the endolysosomal system," Grimm explains.
Particularly interesting candidates in this context are called TPC2 cation channels that may provide the calcium necessary for the fusion of the endosome and lysosome. Therefore, the researchers examined by a new mouse model, which physiological role TPC2 plays in cholesterol processing and what happens to the organism level, if this channel is switched off. It showed: Mice with defective TPC2 Channel rapidly enriched cholesterol in the liver and in the blood plasma, when they received cholesterol enriched feed. Thus they much faster developed a fatty liver or NAFLD than healthy control animals.
Cholesterol accumulation in the cell
This result suggests that the loss of TPC2 leads to defects in cholesterol transport and cholesterol proecessing in the cell. The scientists were able to demonstrate that TPC2 interacts with so-called SNARE proteins that play an important role among others fusion processes in neurons. "Therefore, we suspect that TPC2 regulated or enhanced especially the fusion of the endosomes with lysosomes. If this process does not work anymore, the LDL cholesterol accumulates, because it can not be degraded in lysosomes, " Grimm says.
The increased susceptibility of TPC2 defective mice for NAFLD is clinically highly interesting because NAFLD is the most common chronic liver disease in Western Europe and the United States. In studies, it is estimated that up to 30% of all adults in these countries suffer from NAFLD. In a next step, the researchers want to investigate whether the loss of TPC2 also leads to atherosclerosis or speeds it up, and thus increases the risk for cardiovascular disease. "In the long run, TPC2 could be an attractive target for new therapeutics. If it would be possible to develop synthetic molecules that activate the channel, this would be very interesting for the treatment of NAFLD or for the prevention of cardiovascular sequelae, " Christian Wahl-Schott, Professor at the chair of Pharmacology of Natural Sciences, says.
Synthetic molecules enabling related ion channel
Somehow more advanced on this way is Grimm's team in relation to the so-called TRPML1 cation channel, which belongs to the same protein family as the TPC2 channel and also has an important function in the endolysosomal system: As the scientists recently reported in the journal Nature Communications, they succeded in cooperation with the LMU pharmacist Professor Franz Bracher in developing synthetic molecules by which defective TRPML1 channels can be re-activated in cell experiments in certain cases. TRPML1 channels regulate the cation budget and the pH value in the lysosome and are essential for its proper functioning. Mutated TRPML1 channels cause rare metabolic disease mucolipidosis type IV, which affects the nervous system; most patients can not speak or walk alone. So far, the disease is not treatable, so the newly developed synthetic molecules are a promising approach for new therapeutic possibilities.
The work was carried out within the framework of the Excellence Cluster "Center for Integrated Protein Science Munich" (CIPSM) and is sponsored by the Deutsche Forschungsgemeinschaft (DFG) within the Transregio / SFB 152 "Control of body homeostasis by TRP Channel modules".
Publication: Nature Communications, 2014