- ASSISTANT PROFESSOR Genetics and Genomic Sciences
Cholesterol HomeostasisCholesterol homeostasis is maintained by a plethora of intracellular lipid sensing and trafficking mechanisms, in combination with tight control of its synthesis and catabolism. Many of the processes that influence this homeostasis are poorly understood and these are the focus of my research. To gain insight into key mechanisms of cholesterol homeostasis, initial studies have investigated the functions of two proteins, Niemann-Pick C (NPC)1 and NPC2 that are defective in the human, autosomal recessive disorder, NPC disease. This disorder is characterized by a defect in LDL-derived free cholesterol efflux from the endosomal/lysosomal system, which results in cholesterol accumulation in these intracellular compartments and a progressively debilitating and incurable disease phenotype. Understanding how these proteins function will not only enhance our knowledge regarding the mechanisms that control cholesterol homeostasis but will also aid in the development of treatments for this disorder.
Since the majority of NPC disease patients (95%) have a defect in NPC1, this protein has been the major focus of my studies. We have determined the subcellular localization of NPC1, mapped the topology of this multipolytopic protein and identified key targeting signals within the protein. Further research revealed that NPC1 facilitates the transport of fatty acids across cell membranes, utilizing a proton motive force. These studies indicated that NPC1 was a mammalian member of the well-studied and distantly-related prokaryotic resistance-nodulation-division permeases, the first mammalian protein shown to operate similarly to this evolutionarily ancient superfamily of proteins. Further studies of the precise lipid ligands transported by NPC1 are currently in progress.
Studies to identify homologues of NPC1 have lead to our identification of the NPC1-Like 1 (L1) protein and have expanded our interest in proteins that influence cholesterol homeostasis. Since identifying three alternatively spliced forms of the human form of the protein we have generated an NPC1L1 gene knockout mouse that has alterations in lipid trafficking, including cholesterol transport. In contrast to defects in NPC1 that result in a severe disease phenotype, defects in NPC1L1 actually appear to be beneficial. The NPC1L1 knockout mice appear to be phenotypically normal, although when fed a high-cholesterol diet these mice are clearly resistant to the hypercholesterolemia that occurs in wild-type mice. We have also investigated the tissue expression of NPC1L1 and shown that it is expressed predominantly in the mouse intestine, where it is known to facilitate cholesterol absorption. Interestingly, in humans the highest expression is observed in the liver, although intestinal expression is also higher than in other tissues. Intracellularly, we have localized this protein to Rab 5-positive vesicles. Currently, we are actively investigating the precise role of NPC1L1 in facilitating the transport of cholesterol and other lipids in both humans and mice. This knowledge will aid in the development of treatments for hypercholesterolemia and related disorders.
Ioannou YA, Davies JP. The role of the Niemann-Pick C1-like 1 protein in the subcellular transport of multiple lipids and their homeostasis. Curr Opin Lipidol 2006; 17: 221-226.
Davies JP, Scott C, Ioannou YA, Liapis A, Oishi K. Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia. J Biol Chem; 280: 12710-12720.
Scott C, Ioannou YA, Davies JP, Higgins ME. Targeting of NPC1 to late endosomes requires multiple signals, including one residing within the putative sterol sensing domain. J Biol Chem 2004; 279: 48214-48223.
Walter M, Ioannou YA, Davies JP. Telomerase immortalization upregulates Rab 9 expression and restores LDL-C egress from Niemann-Pick C1 late endosomes. J Lipid Res 2003; 44(2): 243-253.
Davies JP, Ioannou YA, Chen FW. Transmembrane molecular pump activity of Niemann-Pick C1 protein. Science 2000; 290: 2295-2298.
Ioannou YA, Davies JP. Topological analysis of Niemann-Pick C1 protein reveals that the membrane orientation of the putative sterol-sensing domain is identical to those of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein cleavage-activating protein. J Biol Chem 2000; 275: 24367-24374.
Davies JP, Ioannou YA, Levy B. Evidence for a Niemann-pick C (NPC) gene family: identification and characterization of NPC1L1. Genomics 2000; 65: 137-145.
Higgins ME, Ioannou YA, Chen FW, Davies JP. Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol Genet Metab 1999; 68: 1-13.
Chen FW, Ioannou YA, Davies JP. Differential gene expression in apoptosis: identification of ribosomal protein 23K, a cell proliferation inhibitor. Mol Genet Metab 1998; 64: 271-282.
Davies JP, Ioannou YA, Cotter PD. Cloning and mapping of human Rab7 and Rab9 cDNA sequences and identification of a Rab9 pseudogene. Genomics 1997; 41: 131-134.
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Dr. Davies has not yet completed reporting of Industry relationships.
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