Abstract 16650: EDEM3 Modulates the Plasma Triglyceride Level via Its Regulation of LRP1 Expression

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Population genetic studies have provided abundant insight about the development of diseases in all kinds, which has been validated to be instrumental to prioritize biological research and molecular targets for therapeutic intervention. Here we show another example of endoplasmic reticulum (ER) - degradation alpha -mannosidase like protein 3 (EDEM3) in this aspect. We first used a population genetic approach to highlight a variant in the coding region of EDEM3 that is significantly associated with lower blood triglyceride level in a cohort with >30,000 individuals worldwide. Our functional analysis show that the deletion of EDEM3 gene induced a strong uptake of very low-density lipoprotein (VLDL), but not LDL, as a result of up-regulated expression of low-density lipoprotein receptor (LDLR) - related protein 1 (LRP1). We found that the deletion of EDEM3 gene increased more mannose-containing glycoproteins on cell surface, but without altering the sensitivity of cells to ER stress. Our pathway analyses demonstrate that the gene deletion up-regulated the pathways for RNA and ER protein processing and transport, while down-regulated the metabolic pathways, which may help to maintain a normal response to ER stress, and facilitate the processing and transport of the mannose-containing glycoproteins including LRP1 to cell surface. Lipid metabolite analyses reveal a cellular accumulation of TG under EDEM3 deficiency, in particular those with shorter carbon-chains, a profile largely opposite to the one of the plasma from individuals carrying the EDEM3 missense mutation, suggesting that the data from our functional analysis are consistent with the phenotype of genetic perturbation of EDEM3. Thus, our study identifies EDEM3 as a regulator of plasma TG, and targeted inhibition of EDEM3 expression may provide opportunity for plasma TG lowering.