Determine mechanisms for differential regulation of SREBP-1 and SREBP-2 by PC-based feedback

In recent studies, we have found that inactive precursors for SREBP-1 are cleaved, accumulate in the nucleus and activate lipogenic transcription programs when membrane changes linked to low PC levels alter localization of SREBP-activating proteases (see Research Interests). We also found that SREBP-2 was resistant to this regulation (Figure 1), and note that while mouse models of PC depletion are associated with hepatic steatosis, cholesterol levels are not necessarily affected (Jacobs, et al. 2008, JBC). We will determine the mechanisms of this differential regulation which will be important for understanding how lipid or cholesterol synthesis may be inappropriately stimulated in metabolic disease.

Figure 1: Depletion of PC biosynthesis enzymes in HepG2 human hepatoma cells causes nuclear localization of SREBP-1, but not SREBP-2. Yellow line shows cell boundary