ABOUT
Gregory Graf - PH.D.
Dr. Graf's laboratory's research focus is the relationships between obesity and changes in lipid metabolism that link obesity to cardiovascular diseases, diabetes and gall stone formation. Research focuses on the role that transport proteins play in determining whether lipids and cholesterol are stored, metabolized or excreted from the body. By understanding the role of these transport proteins in lipid metabolism and how each is regulated, therapeutic targets for drug development can be identified.
One project focuses on the regulation of a protein complex that reduces cholesterol absorption from the diet and promotes the removal of cholesterol from the body. This complex consists of at least two proteins, ABCG5 and ABCG8. The complex forms as each protein is synthesized and is transported to the cell surface where it is thought to "pump" cholesterol out of the cells that line the small intestine and the channels that direct bile to the gall bladder. The mechanisms that govern the assembly, transport and regulation of this complex are not known. The goal of this project is to elucidate these steps and determine how they might be modified to promote the removal of excess cholesterol from the body.
A second project focuses on the role of ABCD2 in lipid storage. Peroxisomes play a critical role in the metabolism of dietary and endogenously synthesized fatty acids. The entry of fatty acids into peroxisomes is a poorly characterized process that is thought to be mediated by members of the D-subfamily of ABC transporters (ABCD1-D4). ABCD2 (D2) is most highly expressed in brain, adrenal and adipose tissue. D2 expression is stimulated by SREBP-1a and -1c indicating that it is a component of the lipogenic program and suggesting it plays a role in lipid storage in adipose tissue. Interestingly, SREBP-dependent expression of D2 is generally suppressed by liver X receptor (LXR) in liver, but suppression can be relieved by fasting or feeding fibrates. The regulation of D2 expression by two independent transcription factors that are critical to lipid and cholesterol homeostasis indicates that D2 is involved in lipid metabolism in both liver and adipose tissue.
Selected Honors
- Merit Award for Young Investigators, American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology (2002)
- Visiting Distinguished Faculty Fellowship, University of Kentucky (2000)
- Alpha Zeta Agricultural Honor Fraternity (1992)
- Merit Scholarship from San Antonio Livestock Exposition Scholarship, Texas 4H Foundation (1990)
Selected Publications/Presentations
- Sabeva NS, EJ Rouse, GA Graf (2007) Defects in the leptin axis reduce abundance of the ABCG5 ABCG8 sterol transporter in liver The Journal of Biological Chemistry 282:22397-22405
- Zhang DW, GA Graf , R Gerard, JC Cohen, HH Hobbs (2006) Functional asymmetry of nucleotide binding domains in ABCG5 and ABCG8. The Journal of Biological Chemistry 281:4507-16
- GA Graf , JC Cohen and HH Hobbs (2004) Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking. The Journal of Biological Chemistry 279:24881-24888
- GA Graf , L Yu, WP Li, RD Gerard, JC Cohen and HH Hobbs 2003 ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. The Journal of Biological Chemistry 278:48275-48282
- Stangl H, GA Graf , L Yu, G Cao and K Wyne 2002 Effect of estrogen on scavenger receptor BI expression in the rat. Journal of Endocrinology 175:663-672
- GA Graf , WP Li, RD Gerard, I Gelissen, A White, JC Cohen, and HH Hobbs 2002 Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. Journal of Clinical Investigation 110:659-669.
- GA Graf , KR Roswell and EJ Smart 2001 17?-Estradiol promotes the up-regulation of SR-BII in HepG2 cells and in rat livers. J Lipid Research 42: 1444-1449
- Berge, KE, H Tian,GA Graf , L Yu, NV Grishin, J Schultz, P. Kwiterovich, B Shan, R Barnes, HH Hobbs 2000 Accumulation of dietary cholesterol in Sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771-1775
- Burns, PD, GA Graf , SH Hayes, WJ Silvia 2000 Effect of oxytocin on expression of cytosolic phospholipase A2 mRNA and protein in ovine endometrial tissue in vivo. Domestic Animal Endocrinology 19:237-246
- GA Graf , PM Connell, DR van der Westhuyzen and EJ Smart 1999 SR-BI promotes the selective uptake of HDL cholesterol esters into caveolae. The Journal of Biological Chemistry 274:12043-12048