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 protein structural determinants of functional differences between members of the FABP gene family?
- Fatty acids (FA) and monoacylglycerols (MG) 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 intestinal transport and metabolism of FA's and MG's impact whole body energy homeostasis?
- How does the intracellular cholesterol-binding protein, Niemann-Pick type C2 protein (NPC2), function in the transport of cholesterol out of endosomes and lysosomes, and how do NPC2 and NPC1 proteins function together?
The laboratory uses a combination of biochemical, biophysical, cell and molecular biological, and whole animal studies to answer these questions. For example, the structural determinants of the lipid transport properties of FABP and NPC2 proteins are probed using site-directed mutagenesis, fluorescence spectroscopy, and membrane biophysics approaches. Cell culture systems such as the Caco-2 human intestinal cell line 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". Cells 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 preventive 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).
- 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.
- Xu Z, Farver W, Kodukula S, and Storch J. Regulation of sterol transport between membranes and NPC2. Biochemistry 47:11134-43, 2008.
- Storch J and Xu Z. Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking, Biochim Biophys Acta 1791:671-8, 2009.
- 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.
- Chon SH, Douglass JD, Zhou YX, Malik N, Dixon JL, Brinker A, Quadro L and Storch J. Over-Expression of Monoacylglycerol Lipase (MGL) in Small Intestine Alters Endocannabinoid Levels and Whole Body Energy Balance, Resulting in Obesity. PLoS ONE 7(8):e43962. doi: 10.1371/journal.pone.004362, 2012.
- Douglass JD, Malik N, Chon SH, Wells K, Zhou YX, Choi AS, Joseph LB and Storch J. Intestinal mucosal triacylglycerol accumulation secondary to decreased lipid secretion in obese and high fat-fed mice. Frontiers Physiology 3:25. doi: 10.3389/fphys.2012.00025, 2012.
- Lagakos WS, Guan X, Ho SY, Sawicki LR, Corsico B, Murota K, Stark RE, and Storch J. Liver fatty acid-binding protein binds monoacylglycerol in vitro and in mouse liver cytosol. J Biol Chem, 288:19805-15, 2013.
- Gajda AM, Zho YX, Agellon LB, Fried SK, Kodukula S, Fortson W, Patel K, and Storch J. Direct Comparison of Mice Null for Liver- or Intestinal Fatty Acid Binding Proteins Reveals Highly Divergent Phenotypic Responses to High-Fat Feeding. J Biol Chem, 288:30330-30344, 2013.