Understanding the regulation of ER GPATs to control glycerolipid synthesis in disease

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PROJECT SUMMARY Cells are dependent on fatty acids for the generation of membranes and the storage of energy. Within the cell, fatty acids incorporate into membrane and storage glycerolipids through a series of metabolic enzymes. The importance of this process to human health and disease is highlighted by the fact that many metabolic diseases are characterized by dysfunctional lipid accumulation. Despite the importance of glycerolipid synthesis from fatty acids cellular homeostasis and human disease, relatively little is known about the allosteric mechanisms that regulate and control this process. Using CRISPR genetic screens and unbiased lipidomics, the Birsoy lab recently identified calcineurin B homologous protein 1 (CHP1) as a novel regulator of endoplasmic reticulum (ER) glycerolipid synthesis. In this recently published study, our lab showed that loss off CHP1 severely blunted fatty acid incorporation and storage in mammalian cells and invertebrate model organisms. Mechanistically, our lab demonstrated that CHP1 controls glycerolipid synthesis by activating the ER GPAT, GPAT4, the initial rate limiting enzyme for glycerolipid synthesis within the ER. The mechanism by which CHP1 activates GPAT4 is direct, as it was found that CHP1 and GPAT4 form a complex. This work identified CHP1 as one of few regulatory proteins of glycerolipid synthesis described to date. We believe other such regulatory mechanisms control lipid metabolism likely exist. This proposal seeks to more deeply understand the novel biology discovered in our preliminary work and discover additional regulators of ER GPAT activity and function. In Aim 1, we seek to understand the precise mechanism by which CHP1 binds and activates GPAT4. This will provide insight into the posttranslational regulation of lipid metabolism and guide future study of other mechanisms analogous to CHP1. In Aim 2, we will utilize a novel mouse model we recently generated to study ER GPAT function in vivo in both homeostasis and disease such as NASH. In Aim 3, we seek to identify additional mechanisms regulating ER resident GPAT4 through unbiased genetic screening and proteomic approaches. Spanning basic biochemistry to mouse modeling, this application will address outstanding fundamental questions in cellular metabolism and understand this biology in the context of complex diseases afflicting humankind. The innovative studies proposed in this application in addition to the personalized training plan, will provide rigorous postdoctoral training that will prepare me to become an independent investigator.