Project 170932

Lay Abstract Phosphatidylcholine (PC) is the major lipid found in the membranes of mammalian cells. All cells with a nucleus must make PC or the cell will die. Hence, PC is required for life. PC is also the substance that keeps our lungs from collapsing when we breathe out air. PC is required for the formation of lipoproteins (carry cholesterol and fat). We propose to continue our work on PC that has been supported by MRC/CIHR continuously for 34 years. Our recent work has focused on 3 mouse models that have genetic defects in PC biosynthesis. Mice that lack one form of an enzyme called choline kinase (CK) develop muscular dystrophy in their hind legs and have defective bone formation in the front legs. We plan to investigate the mechanisms by which the lack of CK leads to these diseases. Mice that lack another enzyme called CT alpha develop liver disease. We propose studies to determine the mechanism leading to this disease. Lack of a third enzyme, PEMT, leads also to liver disease when the mice are fed a choline-deficient diet. We found that this was due to a decrease in the amount of PC relative to another membrane lipid, PE. We shall investigate to see if this is also true for humans with a liver disease called non-alcoholic steatohepatitis (NASH). We shall obtain the detailed structure of PEMT as a prelude to determination of a specific inhibitor. At the end of the granting period we expect that the information provided will be helpful in development of the treatment for these diseases in humans.

investigating the role of mislocalized cell polarity proteins in tumorigenesis