Lipoprotein Lipase Through the Secretory System

Abstract: Lipoprotein lipase (LPL) reduces triglyceride levels in the blood. Elevated triglyceride levels are a risk factor for heart disease, and triglyceride levels are correlated with insulin resistance in diabetic individuals. Here, we aim to better understand an underappreciated aspect of LPL biology: most of the LPL that is synthesized never makes it out of the cell. Some of this LPL misfolds and can’t escape endoplasmic reticulum (ER) quality control. Additionally, some fully functional LPL is stored in poorly defined secretory vesicles at the periphery of the cell, and this LPL is degraded if cellular signals do not trigger its release. The ER-resident membrane protein Lipase Maturation Factor 1 (LMF1) aids in LPL folding in, and exit from, the ER. Our studies have shown that LMF1 helps to ensure LPL’s disulfide bonds are correctly processed. We don’t know the mechanism by which LMF1 aids in LPL disulfide bond processing, and in Aim 1 we will study LMF1’s structure and function. With respect to the trafficking of LPL stored in secretory vesicles, studies to date indicate that, in adipose tissue, this LPL is secreted in response to insulin signaling. However, we do not fully understand the trafficking itinerary that mobilizes stored LPL for secretion from the cell in response to insulin. In Aim 2, we will explore how vesicles containing stored LPL are selected, mobilized, and released after insulin signaling. Together, these two aims will define the factors and mechanisms that contribute to ensuring LPL’s exit from the cell to the circulation where it can lower triglycerides. Defining these mechanisms will suggest new ways to lower triglycerides and the burden of diabetes and heart disease.