Elevated circulating free fatty acids (FFAs) are a significant risk factor for multiple disease states including obesity, cardiovascular disease, as well as various cancers. In addition, saturated FFAs trigger a cascade of pro-inflammatory signals that promote cellular dysfunction and apoptosis, a condition known as lipotoxicity. Thus, maintaining proper homeostatic control of lipid metabolism is pivotal for optimal cellular function Previous research has suggested that channeling excess cellular FFAs into triglyceride synthesis pathways for energy storage can ameliorate these lipotoxic effects1-3. A key enzyme in this biosynthetic pathway, stearoyl- CoA desaturase (SCD1), converts saturated fatty acids (SFAs) to their monounsaturated fatty acid (MUFA) counterparts as a prelude to triglyceride synthesis and storage as cellular lipid droplets (LDs). Overexpression of SCD1 has been shown to promote LD formation and prevent palmitate-induced lipotoxicity4. Emerging evidence has shown that ER-associated degradation (ERAD) plays a substantial role in regulating cellular lipid metabolism. For example, studies have suggested that mammalian SCD1 is post-translationally degraded through an ERAD pathway, but the details of this mechanism have not been described. My proposed research will: 1) use quantitative proteomics and analytical molecular biology techniques to comprehensively define the ERAD pathway that degrades SCD1, and 2) utilize morphologic and lipidomic approaches to characterize the functional contributions of ERAD and SCD1 degradation to cellular fatty acid metabolism. Together, these studies will advance our current understanding of the post-translational regulation of SCD1, bridge the gap in knowledge between ERAD and fatty acid metabolism, and uncover new strategies in metabolic disease research.
Emerging evidence has shown that various facets of ER-associated degradation (ERAD) play integral roles in cellular fat metabolism. This proposal will define ERAD factors that regulate stearoyl-CoA desaturase (SCD1), a key protein involved in lipid synthesis. Conclusions drawn from these studies may identify potential therapeutic targets for metabolic disease research.
|Huang, Edmond Y; To, Milton; Tran, Erica et al. (2018) A VCP inhibitor substrate trapping approach (VISTA) enables proteomic profiling of endogenous ERAD substrates. Mol Biol Cell 29:1021-1030|