The Neher Lab seeks to better understand the maturation and regulation of a group of human lipases.
We aim to uncover how a membrane-bound maturation factor recognizes and properly folds these lipases so that they can exit the endoplasmic reticulum. We also study how lipase activity is regulated by secreted proteins in response to nutritional state. Our research can potentially impact human health as biochemical deficiencies in lipase activity can cause hypertriglyceridemia and associated disorders, such as diabetes and atherosclerosis. We are an interdisciplinary lab and we study lipase structure-function relationships using a variety of techniques, including membrane protein biochemistry, enzymology, and structural biology.
What we’re working on:
Studies to Improve LPL Function and Stability
LPL is an important therapeutic target that could be delivered to LPL-deficient individuals as a protein or gene therapy drug. We have undertaken studies to enhance its function. First, we aimed to understand how one mutation, LPLS447X, causes a gain-of-function1. This mutation truncates two amino acids from LPL’s C-terminus. Carriers of LPLS447X have decreased VLDL levels and increased HDL levels, a cardioprotective phenotype. It was not known why LPLS447X results in a more favorable serum lipid profile than LPL. We undertook a comprehensive, biochemical comparison of purified LPLS447X and LPL dimers1. We found that LPLS447X enhanced remnant lipoprotein uptake to a greater degree than LPL. We also revealed ways to enhance LPL production2 for use as a protein therapeutic. Additionally, we worked with Gary Pielak’s lab to determine if desiccation tolerance proteins from water bears could stabilize LPL for long-term storage3.
Mechanistic Studies of LPL Inhibitors:
LPL activity is inhibited by a protein known as ANGPTL4, which is induced in adipose tissue in response to fasting. We find that ANGPTL4 directly binds to LPL to inhibit it, and we have use HDX mass spectrometry to identify these binding sites1. We have generated variants of LPL that are resistant to ANGPTL4 inhibition, and we have generated a peptide that blocks the LPL-ANGPTL4 interaction2.
Regulation of LPL Synthesis and Trafficking
LPL activity is regulated by extracellular signaling events. For example, insulin is important for the production and regulated trafficking of LPL. Using adipocytes, we are investigating the trafficking routes and signaling mechanisms involved in normal LPL activity. Using high resolution microscopy and proteomics, we’re exploring the transport of LPL in the tissues that produce it. What does LPL trafficking look like?