The purpose of the project is to find out how microbial molecules, such as bacterial lipopolysaccharides, induce the accumulation of triglycerides (i.e., fat droplets) in macrophages. This process is important for the pathogenesis of the foamy macrophages that are found at sites of infection (especially within granulomas) and in arterial walls (where macrophages contribute substantially to atherosclerosis). In FY 2014 we showed that Toll-like receptor agonists (i.e. bacterial molecules such as lipopolysaccharides) induce cultured macrophages to retain triglyceride in lipid droplets. We defined the 3 molecular mechanisms that participate in this phenomenon. We further showed that an important contributor, previously unexpected, is the pH of the culture medium. By inducing cells to secrete acids that lower the medium pH, both TLR agonists and low oxygen tension promote triglyceride storage and decrease cell metabolism in general. These changes are very similar to those reported in the tissues of organs affected by severe sepsis, and we hope to study this possible connection in more detail.
