Transcriptional regulation of lipid homeostasis in Drosophila

The ability to sense metabolic status and coordinately regulate specific aspects of metabolism is central to human health and disease. The second chapter of this dissertation defines a role for the Drosophila nuclear receptor, DHR96, as a key regulator that coordinates triacylglycerol (TAG) and cholesterol homeostasis. Studies presented in this dissertation show that DHR96 maintains whole animal TAG levels by promoting the breakdown of dietary TAG through regulation of the intestinal lipase Magro. Previous studies have shown that DHR96 binds cholesterol in its ligand-binding domain and regulates the transcriptional response to dietary cholesterol. The third chapter of this dissertation describes how, in conjunction with its role in promoting dietary TAG digestion, DHR96 functions through magro to prevent the accumulation of excess sterols in the fly. Magro exerts this role in cholesterol homeostasis through its cholesterol esterase activity, cleaving stored cholesterol esters to promote sterol excretion. Taken together, these studies define a key role for DHR96 in coordinating dietary TAG digestion and maintaining cholesterol homeostasis through its regulation of magro. Observations made during my studies of Drosophila lipid metabolism suggested that the metabolic state of the progeny is dependent on the health and nutritional status of their parents. The fourth chapter of this dissertation shows that temporary dietary restriction during the parental iv generation influences TAG and glycogen levels in the resulting progeny, as well as specific changes in metabolic gene expression. This work also defines roles for both DHR96 and HP1 as key regulators of these transgenerational effects on metabolism, suggesting that transcriptional regulation and chromatin are a central part of this pathway. Overall, these studies establish a new genetic system and framework for detailed molecular characterization of the mechanisms that facilitate the transgenerational regulation of metabolism, including an investigation of nuclear receptor and chromatin factors in this process.