About

Saskia Neher is an associate professor in Biochemistry and Biophysics at the University of North Carolina at Chapel Hill. She completed her undergraduate studies at the University of Oregon, where she worked in Dr. Diane Hawley’s lab. During graduate school at MIT, she worked in Tania Baker’s lab using proteomic methods to study substrate selection by the ClpXP protease. Her postdoctoral research was conducted in Peter Walter’s lab at UCSF, where she studied SRP-dependent protein targeting. During this time, she initiated a project focused on understanding how interacting factors influence the folding and activity of a group of mammalian lipases, a research direction that her lab continues at UNC Chapel Hill. She is also a member of the McAllister Heart Institute, the Nutrition and Obesity Research Center, and the graduate program in Cell Biology.

Research topics

• Biochemistry
• Chemistry
• Internal medicine
• Polymer chemistry
• Endocrinology
• Biology
• Medicine
• Biophysics

Selected publications

• Functional characterization of Furin-mediated lipoprotein lipase cleavage

  Disease Models & Mechanisms · 2026-05-21

  articleOpen accessSenior author

  Lipoprotein lipase (LPL) is the rate-limiting enzyme that hydrolyzes triglycerides within circulating lipoproteins. LPL dysfunction leads to familial LPL deficiency, which is characterized by chylomicronemia and high risk for acute pancreatitis. Although cell culture studies indicate that the protease furin inactivates LPL by cleavage, the physiological relevance of this process remains unclear. In this study, we investigated the impact of furin-mediated LPL cleavage in vivo using inducible knockout mouse models and gene therapy. After identifying the tissue-specific prevalence of LPL cleavage, we compared mice expressing a furin-resistant LPL mutant versus furin-sensitive LPL. Our results demonstrate that furin-resistant LPL lowers longitudinal plasma triglyceride levels without causing adverse effects such as hepatic steatosis. These findings highlight that engineered furin resistance is a viable strategy to enhance LPL's metabolic function.

  PublisherDOI

• ApoJ regulates endothelial lipase activity and stability

  UNC Libraries · 2026-04-10

  articleOpen access

  Endothelial lipase (EL) is a key regulator of high-density lipoprotein (HDL) metabolism. Many aspects of EL function remain incompletely understood due to challenges in purifying active EL. This study identifies apolipoprotein J (ApoJ) as a novel chaperone for EL, crucial for its solubility and activity. Using an optimized purification protocol that yields active EL, we discovered that ApoJ consistently co-purifies with EL, maintaining its activity. We further show that knocking down ApoJ decreases the activity of EL. We demonstrate that ApoJ interacts with EL via its hydrophobic lid and tryptophan loop regions, and that mutating these regions abolishes the effect of ApoJ on the solubility and activity of EL. We show that ApoJ, EL, and ApoA1 (the defining lipoprotein of HDL particles) colocalize in HDL particles in mouse plasma. However, we find that ApoJ is not a direct carrier for EL to HDL particles. Instead, our data suggest that ApoJ primarily serves to enhance EL activity through its role as a chaperone, even when incorporated into lipid substrates. Our findings suggest a model in which ApoJ protects EL in plasma and enhances its hydrolysis of lipoprotein substrates. We propose that ApoJ is an accessory protein for EL, analogous to GPIHBP1 for LPL and co-lipase for PL. Further study of the interaction between EL and ApoJ will promote a better understanding of HDL metabolism.

  PublisherDOI

• <scp>ApoJ</scp> regulates endothelial lipase activity and stability

  Protein Science · 2026-03-02

  articleOpen accessSenior authorCorresponding

  Endothelial lipase (EL) is a key regulator of high-density lipoprotein (HDL) metabolism. Many aspects of EL function remain incompletely understood due to challenges in purifying active EL. This study identifies apolipoprotein J (ApoJ) as a novel chaperone for EL, crucial for its solubility and activity. Using an optimized purification protocol that yields active EL, we discovered that ApoJ consistently co-purifies with EL, maintaining its activity. We further show that knocking down ApoJ decreases the activity of EL. We demonstrate that ApoJ interacts with EL via its hydrophobic lid and tryptophan loop regions, and that mutating these regions abolishes the effect of ApoJ on the solubility and activity of EL. We show that ApoJ, EL, and ApoA1 (the defining lipoprotein of HDL particles) colocalize in HDL particles in mouse plasma. However, we find that ApoJ is not a direct carrier for EL to HDL particles. Instead, our data suggest that ApoJ primarily serves to enhance EL activity through its role as a chaperone, even when incorporated into lipid substrates. Our findings suggest a model in which ApoJ protects EL in plasma and enhances its hydrolysis of lipoprotein substrates. We propose that ApoJ is an accessory protein for EL, analogous to GPIHBP1 for LPL and co-lipase for PL. Further study of the interaction between EL and ApoJ will promote a better understanding of HDL metabolism.

  PublisherDOI

• Cryogenic electron tomography reveals helical organization of lipoprotein lipase in storage vesicles

  Science Advances · 2025-08-06

  articleOpen accessSenior authorCorresponding

  Lipoprotein lipase (LPL) is a triglyceride lipase that is contained in intracellular vesicles in an inactive storage form before secretion, but the precise structural details have not yet been resolved. Using cryo-electron tomography (cryo-ET), we observe that LPL exists inside of storage vesicles as a filament with an 11-nanometer diameter and is packed in these vesicles in two distinct patterns. Next, we solved a 4.2-Å resolution cryo-electron microscopy (cryo-EM) structure of this 11-nanometer LPL filament using purified protein. The filament is made of repeating pairs of LPL molecules with occluded active sites, rendering the LPL inactive. The comparison of the in situ subtomogram average and the in vitro cryo-EM structure indicates that the previously uncharacterized physiological storage form of LPL is an inactive filament.

  PublisherDOI

• Macromolecular Interactions of Lipoprotein Lipase (LPL)

  Sub-cellular biochemistry/Subcellular biochemistry · 2024-01-01 · 14 citations

  reviewSenior author
  PublisherDOI

• Abstract 2392 Structural and biochemical characterization of the essential lipoprotein lipase inhibitor complex, ANGPTL3/8

  Journal of Biological Chemistry · 2024-03-01 · 1 citations

  articleOpen accessSenior author

  Lipoprotein lipase (LPL) is an enzyme that hydrolyzes large triglyceride-containing lipoprotein particles into free fatty acids that can be taken up by adipose or muscle cells for energy storage or use. LPL activity is inhibited by members of the angiopoietin-like (ANGPTL) protein family, which includes ANGPTL3 and ANGPTL4, both of which can form a multimeric complex with ANGPTL8. While it is known that the ANGPTL3/8 complex is a more potent inhibitor than ANGPTL3 alone, we lack macromolecular information on the ANGPTL3/8 complex that can be useful in understanding its interaction with LPL. In this study, we used a novel method to co-purify N-terminal ANGPTL3 and ANGPTL8 from mammalian cells. Our purification strategy allowed us to obtain ANGPTL3/8 complex products rather than the individual proteins. We characterized our complex with mass photometry and size-exclusion chromatography with multi-angle light scattering. Our study showed that the oligomeric state of the ANGPTL3/8 complex is in a 3 to 1 ratio of ANGPTL3 to ANGPTL8, respectively. The ANGPTL3/8 complex purified from Expi293 cells also inhibits LPL potently in activity assays using native LPL substrate, with IC50 values in the low nanomolar range. This data can be used to further understand the regulation of triglyceride levels in the blood plasma by LPL and ANGPTL3 and ANGPTL8 and allow for the development of small molecule inhibitors of ANGPTL3/8 to treat patients with hypertriglyceridemia.

  PublisherOA PDFDOI

• Structure of Dimeric Lipoprotein Lipase Reveals a Pore for Hydrolysis of Acyl Chains

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-03-22 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Lipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which is a risk factor for cardiovascular disease (CVD). Using cryogenic electron microscopy (cryoEM), we determined the structure of an active LPL dimer at 3.9 Ã… resolution. This is the first structure of a mammalian lipase with an open, hydrophobic pore adjacent to the active site. We demonstrate that the pore can accommodate an acyl chain from a triglyceride. Previously, it was thought that an open lipase conformation was defined by a displaced lid peptide, exposing the hydrophobic pocket surrounding the active site. With these previous models after the lid opened, the substrate would enter the active site, be hydrolyzed and then released in a bidirectional manner. It was assumed that the hydrophobic pocket provided the only ligand selectivity. Based on our structure, we propose a new model for lipid hydrolysis, in which the free fatty acid product travels unidirectionally through the active site pore, entering and exiting opposite sides of the protein. By this new model, the hydrophobic pore provides additional substrate specificity and provides insight into how LPL mutations in the active site pore may negatively impact LPL activity, leading to chylomicronemia. Structural similarity of LPL to other human lipases suggests that this unidirectional mechanism could be conserved but has not been observed due to the difficulty of studying lipase structure in the presence of an activating substrate. We hypothesize that the air/water interface formed during creation of samples for cryoEM triggered interfacial activation, allowing us to capture, for the first time, a fully open state of a mammalian lipase. Our new structure also revises previous models on how LPL dimerizes, revealing an unexpected C-terminal to C-terminal interface. The elucidation of a dimeric LPL structure highlights the oligomeric diversity of LPL, as now LPL homodimer, heterodimer, and helical filament structures have been elucidated. This diversity of oligomerization may provide a form of regulation as LPL travels from secretory vesicles in the cell, to the capillary, and eventually to the liver for lipoprotein remnant uptake. We hypothesize that LPL dimerizes in this active C-terminal to C-terminal conformation when associated with mobile lipoproteins in the capillary.

  PublisherOA PDFDOI

• Structure of dimeric lipoprotein lipase reveals a pore adjacent to the active site

  Nature Communications · 2023 · 24 citations

  Senior authorCorresponding
  • Chemistry
  • Biochemistry

  Lipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which is a risk factor for cardiovascular disease (CVD). Using cryogenic electron microscopy (cryoEM), we determined the structure of an active LPL dimer at 3.9 Å resolution. This structure reveals an open hydrophobic pore adjacent to the active site residues. Using modeling, we demonstrate that this pore can accommodate an acyl chain from a triglyceride. Known LPL mutations that lead to hypertriglyceridemia localize to the end of the pore and cause defective substrate hydrolysis. The pore may provide additional substrate specificity and/or allow unidirectional acyl chain release from LPL. This structure also revises previous models on how LPL dimerizes, revealing a C-terminal to C-terminal interface. We hypothesize that this active C-terminal to C-terminal conformation is adopted by LPL when associated with lipoproteins in capillaries.

  PublisherOA PDFDOI

• Abstract 2529: CryoEM Yields New Insights into Lipoprotein Lipase Structure and Function

  Journal of Biological Chemistry · 2023-01-01

  articleOpen access1st authorCorresponding
  PublisherDOI

• Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions

  PLoS ONE · 2023-04-12 · 12 citations

  articleOpen accessCorresponding

  Lipoprotein lipase (LPL), a crucial enzyme in the intravascular hydrolysis of triglyceride-rich lipoproteins, is a potential drug target for the treatment of hypertriglyceridemia. The activity and stability of LPL are influenced by a complex ligand network. Previous studies performed in dilute solutions suggest that LPL can appear in various oligomeric states. However, it was not known how the physiological environment, that is blood plasma, affects the action of LPL. In the current study, we demonstrate that albumin, the major protein component in blood plasma, has a significant impact on LPL stability, oligomerization, and ligand interactions. The effects induced by albumin could not solely be reproduced by the macromolecular crowding effect. Stabilization, isothermal titration calorimetry, and surface plasmon resonance studies revealed that albumin binds to LPL with affinity sufficient to form a complex in both the interstitial space and the capillaries. Negative stain transmission electron microscopy and raster image correlation spectroscopy showed that albumin, like heparin, induced reversible oligomerization of LPL. However, the albumin induced oligomers were structurally different from heparin-induced filament-like LPL oligomers. An intriguing observation was that no oligomers of either type were formed in the simultaneous presence of albumin and heparin. Our data also suggested that the oligomer formation protected LPL from the inactivation by its physiological regulator angiopoietin-like protein 4. The concentration of LPL and its environment could influence whether LPL follows irreversible inactivation and aggregation or reversible LPL oligomer formation, which might affect interactions with various ligands and drugs. In conclusion, the interplay between albumin and heparin could provide a mechanism for ensuring the dissociation of heparan sulfate-bound LPL oligomers into active LPL upon secretion into the interstitial space.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R00HL098277

  NIH · $723k · 2014

• Investigation of the Molecular Mechanisms of Lipoprotein Lipase Inhibitors

  NIH · $383k · 2015–2025

• Investigation of the Molecular Mechanisms of Lipoprotein Lipase Inhibitors

  NIH · $3.4M · 2015–2026

Frequent coauthors

• Tania A. Baker

  Massachusetts Institute of Technology

  17 shared

• Peter Walter

  University of California, San Francisco

  13 shared

• Kathryn H. Gunn

  University of North Carolina at Chapel Hill

  9 shared

• Robert T. Sauer

  Massachusetts Institute of Technology

  9 shared

• Niels Bradshaw

  Brandeis University

  9 shared

• Lindsey J. Broadwell

  University of Colorado Boulder

  7 shared

• Melissa A. Babilonia-Rosa

  7 shared

• Julia M. Flynn

  University of Massachusetts Chan Medical School

  6 shared

Labs

• Neher LabPI

  The Neher Lab studies the biophysics of synaptic transmission and the role of electrical signaling in neural circuits.

Education

• Postdoctoral fellow, Biochemistry and Biophysics

  University of California, San Francisco

  2011

Awards & honors

• National Lipid Assoc. Jr. Faculty Research Award (2017)
• Kavli Fellow (2014)
• Pew Scholar in the Biomedical Sciences (2012)
• NIHK99/R00 Pathway to Independence Award (2010)
• Jane Coffin Childs Fellow (2006)