Judith Storch, Ph.D.
Ph.D., Columbia University, 1983
Lipids such as fatty acids and cholesterol are involved in innumerable cellular processes, including energy storage and production, membrane biogenesis, signal transduction, and the regulation of gene expression. Nevertheless, the mechanisms by which lipids are transported and targeted within cells remain largely unknown. Abnormal lipid trafficking, such as that occurring in lipid-storage diseases, can lead to severe cellular pathologies. The overall focus of research in this laboratory is on lipid traffic in cells, with particular emphasis on long-chain fatty acids, monoacylglycerols, and cholesterol. Ongoing efforts are addressing the following questions:
- What are the functions of cytoplasmic fatty acid-binding proteins (FABP) in intracellular lipid transport and metabolism? Why do different cell types have different FABP?
- What are the structural determinants of functional differences between members of the FABP gene family? What are the mechanisms of fatty acid and monoacylglycerol transport and utilization in polarized intestinal epithelial cells?
- Fatty acids and monoacylglycerols delivered to the intestinal cell via the diet or via the bloodstream are metabolized differently--how is this 'metabolic polarity' established and maintained?
- How does the intracellular
cholesterol-binding protein, Niemann-Pick type C2 protein (NPC2),
function in the transport of cholesterol out of endosomes and
Figure: Tertiary structure of the heart fatty acid binding protein. The helix-turn-helix domain (shown in pink) is hypothesized to be important in fatty acid (shown in blue) transfer to membranes.
The laboratory uses a combination of biochemical, biophysical, cell and molecular biological approaches to answer these questions. For example, fluorescence spectroscopic analysis of recombinant FABP is used to examine the interactions of fatty acids with FABP and the kinetics of fatty acid and monoacylglycerol transfer between FABP and membranes. The structural determinants of ligand-protein interactions and FABP-membrane interactions are probed using chemical modification and site-directed mutagenesis. Cell culture systems such as the Caco-2 human intestinal cell line and 3T3-L1 adipocytes are used to examine cellular lipid transport using biochemical methods and confocal microscopy. The functions of FABPs are also studied using transgenic mouse models in which specific FABP expression has been "knocked out" and in cultured cells by manipulation of FABP content. The metabolic polarity of fatty acid and monoacylglycerol in the intestinal cell is studied using a variety of mouse models and cell culture approaches. Human fibroblasts from patients with NPC disease are used to examine the function of the NPC2 protein in cholesterol trafficking. These studies are providing fundamental information about the cellular trafficking of lipids , with the ultimate goal of enabling effective preventice and therapeutic approaches to a variety of pathologic conditions including obesity, cardiovascular disease, and lipid-storage diseases.
Cheruku SR, Xu Z, Dutia R, Lobel P and Storch J. Mechanism of cholesterol transfer from the Niemann-
Pick type C2 protein to model membranes supports a role in lysosomal cholesterol transport. J Biol
Chem 281: 31594-31604, 2006 (selected as JBC paper of the week 10/20/06)
Chon SH, Zhou YX, Dixon JL, and Storch J. Intestinal monoacylglycerol metabolism: Developmental and
nutritional regulation of monoacylglycerol lipase and monoacylglycerol acyltransferase. J Biol
Chem 282:33346-57, 2007.
Storch J and Corsico B. The emerging functions and mechanisms of the mammalian fatty acid-binding
proteins. Ann Rev Nutrition 28:73-95, 2008.
Storch J, Zhou YX and Lagakos WS. Metabolism of apical vs. basolateral sn-2-monoacylglycerol and fatty acids in rodent small intestine. J Lipid Res 49:1762-69, 2008.
Storch J and Xu Z. Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking, Biochim Biophys
Acta 1791:671-8, 2009.
Karsenty J, Helal O, Lechène de la Porte P, Beauclair-Deprez P, Martin-Elyazidi C, Planells R, Storch J, and
Gastaldi M. I-FABP expression alters the intracellular distribution of the BODIPY C16 fatty acid
analog. Mol Cell Biochem 326:97-104, 2009.
Siddiqi S, Saleem U, Abumrad N, Davidson N, Storch J, Siddiqi S, Mansbach CM. A Novel Multi-protein
Complex Is Required for the Generation of the Prechylomicron Transport Vesicle from Intestinal ER.
J Lipid Res, 51:1918-28, 2010.
Lagakos WS, Gajda, A, Agellon L, Binas B, Choi V, Mandap B, Russnak T, Zhou YX, and Storch J. Different
functions of the intestinal- and liver-type fatty acid-binding proteins (FABP) in the intestine and in
whole body energy homeostasis. Am J Physiology 300:G803-14, 2011.
McCauliff L, Xu Z, and Storch J. Sterol transfer between cyclodextrin and membranes: Similar but not
identical mechanism to NPC2-mediated cholesterol transfer. Biochemistry 50:7341-9, 2011.