Choline. A nutrient that is involved in the regulation of cell proliferation, cell death, and cell transformation.

Choline deficiency causes hepatocyte proliferation, apoptosis and transformation. Thus, it is an excellent model in which to study the molecular mechanisms underlying these processes. Several interesting questions can be addressed. What is the first event that begins the cells on the path towards transformation? Is it triggered by some autocrine factor produced in choline depleted cells? Does it involve alteration of DNA structure with subsequent apoptosis, compensatory cell proliferation, and enhanced survival of preneoplastic cells? Is there a specific choline deficiency signal which triggers apoptosis, with subsequent compensatory cell proliferation in a methyl-deficient environment causing hypomethylation of DNA? Does this result in abnormal transcription of genes with resulting transformation? Or is the activation of PKC the first event? PKC-mediated cell proliferation might then be balanced by down regulation of growth factor response, withdrawal of which causes apoptosis. The ensuing high rate of cell turnover might result in the survival and replication of preneoplastic cells. Multiple alternative variations of these questions exist. Whatever the critical first event is, our models also allow us to ask about molecular differences between cells that pass through these early events and those that do not. At first glance, choline deficiency may seem to be an artificial situation that might rarely occur in nature. However, the answers to some of the above questions will help us to understand how changes in gene expression and the signaling pathways that are fundamental for many cell functions, might be involved in liver cell proliferation, death and transformation.