Analysis of the function and subcellular localization of FAT/CD36 in hepatocytes and transfected cell lines of hepatic and non-hepatic origin.

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dc.contributor.advisorMayrhofer, Grahamen
dc.contributor.advisorCleland, Leslie Glenen
dc.contributor.authorEyre, Nicholas Stratforden
dc.contributor.schoolSchool of Molecular and Biomedical Science : Microbiology and Immunologyen
dc.date.issued2007en
dc.description.abstractThe class B scavenger receptor CD36, or fatty acid translocase (FAT), is an 88 kDa plasma membrane glycoprotein that is the founding member of the class B scavenger receptor family. It has a number of natural ligands and has different functions at various locations in the body. It contributes to adhesion of platelets via its binding to thrombospondin-1. In monocytes and macrophages, it contributes to recognition and phagocytosis of apoptotic cells and it mediates the binding and uptake of oxidatively damaged low-density lipoproteins (oxLDL). In adipose and muscle tissues, FAT/CD36 mediates high-affinity binding and uptake of long-chain fatty acids (LCFAs) and is therefore a key regulator of lipid storage (particularly in adipocytes) and mitochondrial beta oxidation (particularly in muscle). Interestingly FAT/CD36 also binds native lipoproteins (including high-density lipoproteins [HDL]) with high affinity in vitro, although the physiological significance of this is unclear at present. Expression of FAT/CD36 by hepatocytes has not been recognised until recently, mainly because it is gender-regulated in both humans, and rats. However, the primary function of FAT/CD36 in the liver is unknown. The work described in this thesis has used various transfected cell lines to examine the possibility that FAT/CD36 contributes to hepatic LCFA uptake and/or the uptake of cholesteryl esters (and other lipids) from HDL. The subcellular localization of FAT/CD36 has been explored in rat liver and in cell lines of hepatic and non-hepatic origin, especially with respect to its association with specialized plasma membrane lipid raft microdomains known as caveolae. Furthermore, the importance of the cytoplasmic carboxyl-terminus of FAT/CD36 in both subcellular localization of the molecule and its activity as a LCFA transporter has been examined using truncated mutants and chimeric variants of FAT/CD36. The results indicate that FAT/CD36 contributes to LCFA uptake by hepatocyte-derived cell lines. In these cells it resides in both non-raft and lipid raft domains of the plasma membrane that may not always include caveolae. The studies also indicate that the cytoplasmic C-terminus of FAT/CD36 contributes to the attachment of FAT/CD36 to membranes, including raft-derived detergent-resistant membranes. This domain is necessary also for correct targeting of the receptor to the plasma membrane and for its activity as a LCFA transporter. Finally, DNA constructs have been prepared and tested, with the objective of producing transgenic mice in which expression of FAT/CD36 can be induced and over-expressed specifically in the liver. This model could be used to confirm whether FAT/CD36 has a role as a LCFA transporter in the liver and to explore whether it has additional significance as a hepatic transporter of HDL-derived cholesteryl esters or as a scavenger of oxidised LDL.en
dc.description.dissertationThesis (Ph.D.) -- School of Molecular and Biomedical Science, 2007en
dc.identifier.urihttp://hdl.handle.net/2440/47787
dc.provenanceCopyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.en
dc.subject.lcshFatty acids.en
dc.subject.lcshGlycoproteins.en
dc.subject.lcshBiochemistry.en
dc.titleAnalysis of the function and subcellular localization of FAT/CD36 in hepatocytes and transfected cell lines of hepatic and non-hepatic origin.en
dc.typeThesisen

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