UCSF

Regulation of nutrient consumption and storage is a complex process requiring numerous interconnected genetic pathways that monitor and respond to both environmental and internal conditions. Though we have a good framework understanding of some of the basic modules of this network, our grasp of the intricate regulation of these processes remains limited.

We have utilized the model organism C. elegans to investigate the genetic pathways regulating nutrient storage. To monitor nutritional status of these animals, we have utilized a number of previously described assays, and have adapted and improved others, described in chapter II. By visually monitoring aspects of nutrient storage, while simultaneously manipulating genes, either individually or in combinations, we have described a novel pathway regulating lipid storage, described in chapter III, and have begun work on a second pathway which appears to regulate the cell biology of a nutrient storage compartment, described in chapter IV.

In a forward genetic screen for genes regulating lipid storage, we isolated a mutation in acs-3, encoding a long chain fatty acyl-CoA synthase. These mutants exhibit elevated lipid staining intensity, and abnormally large intestinal lipid droplets. Our characterization of this gene revealed that it is expressed in a limited set of tissues, and expression of acs-3 in the hypodermal seam cells, a stem cell-like population, is sufficient to rescue the abnormal lipid storage of mutant animals. We performed both unbiased and candidate suppressor screens, and identified a set of genes that function in the acs-3 pathway to regulate nutrient storage. Our findings suggest a pathway in which acs-3, acdh-10, acdh-11 and elo-6 function to modulate fatty acyl-CoA levels, which in turn regulate nhr-25 function, perhaps as components of nhr-25 ligands.

The work described here sheds light on networks of genes that likely function in different tissues to regulate nutrient storage in a concerted fashion. In addition, these findings underscore the utility of genetic interrogation of metabolic networks, and demonstrate that enzymes with well-understood enzymatic activities can function in unexpected ensembles to modulated metabolism via unpredictable mechanisms.