Gregory Graf, Ph.D.

Bio / Education: 


PhD:               Physiology, University of Kentucky, Lexington, KY
Fellowship:     Molecular Genetics, University of Texas Southwestern Medical School at Dallas, TX

Research Description: 


Dr. Graf's laboratory's research focus is on the relationships between obesity and changes in lipid and lipoprotein metabolism that link obesity to cardiovascular diseases and diabetes. 

Our work largely centers on pathways that promote the active elimination of cholesterol from the body in a process termed “Reverse Cholesterol Transport”.  Currently available therapies target cholesterol synthesis and absorption to reduce plasma cholesterol and lower the risk cardiovascular disease.  However, an emerging body of work suggests that the flux of cholesterol through lipoproteins (LDL and HDL) is more relevant to cardiovascular disease than their absolute levels in plasma.  In addition, research from our lab and others suggests that cholesterol in the liver may play an active role in the development of non-alcoholic fatty liver disease, a common complication of obesity. 

A transport protein complex called ABCG5 ABCG8, or G5G8 for short, is expressed in both the liver and intestine and represents the major route for cholesterol elimination from the body.  We have recently shown that the loss of this transporter worsens the development of fatty liver disease and that acutely increasing its levels can restore some aspects of liver function in a mouse model of obesity and fatty liver disease.  Our data also suggests that the function of this pump is altered in the setting of insulin resistance and fatty liver. However, little is known about the mechanisms that govern these changes and the extent to which these changes affect the progression of disease.  The goal of this project is to determine how this pump is regulated in the liver such that therapeutics can be developed to accelerate cholesterol elimination in the treatment of both cardiovascular and liver disease. 

The second project focuses on the role of the intestine in cholesterol elimination.  Classically, we think of the small intestine as an absorptive organ that provides the body with the nutrients extracted from our diets.  However, it is clear that this organ is also important in cholesterol elimination and that other pathways independent of G5G8 contribute to sterol excretion.  The goal of this project is to identify proteins within this alternate pathway and determine whether these are amenable to pharmaceutical development.

Selected Publications: 


1. D Coy, C Wooten-Kee, NS Sabeva, GA Graf and M Vore 2010 ABCG5/ABCG8-Independent Biliary Cholesterol Excretion in Lactating Rats American Journal of Physiology - Gastrointestinal and Liver Physiology 299:G228-35 (PMID: 20413720)

2. NS Sabeva, CM McPhaul, EJ Rouse, X Li, and GA Graf 2011 Phytosterols differentially influence ABC transporter expression, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells. The Journal of Nutritional Biochemistry 22:777-83 (PMID: 21111593)

3. J Liu, S Liang, X Liu, JA Brown, KE Newman, M Sunkara, AJ Morris, S Bhatnagar, X Li, A Pujol and GA Graf 2012 The absence of ABCD2 sensitizes mice to disruptions in lipid metabolism by dietary erucic acid The Journal of Lipid Research 53:1071(PMID:22493092)

4. K Su, NS Sabeva, J Liu, Y Wang, S Bhatnagar, DR. van der Westhuyzen and GA Graf 2012 The ABCG5 ABCG8 sterol transporter opposes the development of fatty liver disease and loss of glycemic control independent of phytosterol accumulation. The Journal of Biological Chemistry 287:28564 (PMID:2271510)

5. K Su, NS Sabeva, JD Lester, J Liu, S Liang, GA Graf 2014 Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice. Arteriosclerosis, Thrombosis and Vascular Biology 34:26-33 (PMCID: PMC4096285)

6. X Liu, J Liu, S Liang, A Schlüter, S Fourcade, S Aslibekyan, A Pujol, GA Graf 2014 ABCD2 alters peroxisome proliferator-activated receptor α signaling in vitro, but does not impair responses to fenofibrate therapy in a mouse model of diet-induced obesity. Molecular Pharmacology 86:505-13 (PMID: 25123288)

PubMed Publications: 

  • Pijut, S.S.;Corbett, D.E.;Wang, Y.;Li, J.;Charnigo, R.J.;Graf, G.A. "Effect of peripheral circadian dysfunction on metabolic disease in response to a diabetogenic diet." American journal of physiology. Endocrinology and metabolism 310, 11 (2016): E900-11. [PubMed Link] | [ Full text ]
  • Wang, Y.;Su, K.;Sabeva, N.S.;Ji, A.;Westhuyzen, D.R.;Foufelle, F.;Gao, X.;Graf, G.A. "GRP78 rescues the ABCG5 ABCG8 sterol transporter in db/db mice." Metabolism: clinical and experimental 64, 11 (2015): 1435-43. [PubMed Link] | [ Full text ]
  • Liu, X.;Liu, J.;Lester, J.D.;Pijut, S.S.;Graf, G.A. "ABCD2 identifies a subclass of peroxisomes in mouse adipose tissue." Biochemical and biophysical research communications 456, 1 (2015): 129-34. [PubMed Link] | [ Full text ]
  • Wang, Y.;Liu, X.;Pijut, S.S.;Li, J.;Horn, J.;Bradford, E.M.;Leggas, M.;Barrett, T.A.;Graf, G.A. "The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination." Journal of lipid research 56, 4 (2015): 810-20. [PubMed Link] | [ Full text ]
  • Liu, X.;Liu, J.;Liang, S.;Schlüter, A.;Fourcade, S.;Aslibekyan, S.;Pujol, A.;Graf, G.A. "ABCD2 alters peroxisome proliferator-activated receptor α signaling in vitro, but does not impair responses to fenofibrate therapy in a mouse model of diet-induced obesity." Molecular pharmacology 86, 5 (2014): 505-13. [PubMed Link] | [ Full text ]
  • Su, K.;Sabeva, N.S.;Wang, Y.;Liu, X.;Lester, J.D.;Liu, J.;Liang, S.;Graf, G.A. "Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice." Arteriosclerosis, thrombosis, and vascular biology 34, 1 (2014): 26-33. [PubMed Link] | [ Full text ]
  • Salous, A.K.;Panchatcharam, M.;Sunkara, M.;Mueller, P.;Dong, A.;Wang, Y.;Graf, G.A.;Smyth, S.S.;Morris, A.J. "Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice." Journal of lipid research 54, 10 (2013): 2775-84. [PubMed Link] | [ Full text ]
  • Meyer, J.M.;Graf, G.A.;Westhuyzen, D.R. "New developments in selective cholesteryl ester uptake." Current opinion in lipidology 24, 5 (2013): 386-92. [PubMed Link] | [ Full text ]
  • Liu, J.;Liang, S.;Liu, X.;Brown, J.A.;Newman, K.E.;Sunkara, M.;Morris, A.J.;Bhatnagar, S.;Li, X.;Pujol, A.;Graf, G.A. "The absence of ABCD2 sensitizes mice to disruptions in lipid metabolism by dietary erucic acid." Journal of lipid research 53, 6 (2012): 1071-9. [PubMed Link] | [ Full text ]
  • Su, K.;Sabeva, N.S.;Liu, J.;Wang, Y.;Bhatnagar, S.;Westhuyzen, D.R.;Graf, G.A. "The ABCG5 ABCG8 sterol transporter opposes the development of fatty liver disease and loss of glycemic control independently of phytosterol accumulation." The Journal of biological chemistry 287, 34 (2012): 28564-75. [PubMed Link] | [ Full text ]
  • Ghoshal, S.;Trivedi, D.B.;Graf, G.A.;Loftin, C.D. "Cyclooxygenase-2 deficiency attenuates adipose tissue differentiation and inflammation in mice." The Journal of biological chemistry 286, 1 (2011): 889-98. [PubMed Link] | [ Full text ]
  • Sabeva, N.S.;McPhaul, C.M.;Li, X.;Cory, T.J.;Feola, D.J.;Graf, G.A. "Phytosterols differentially influence ABC transporter expression, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells." The Journal of nutritional biochemistry 22, 8 (2011): 777-83. [PubMed Link] | [ Full text ]
  • Liu, J.;Sabeva, N.S.;Bhatnagar, S.;Li, X.A.;Pujol, A.;Graf, G.A. "ABCD2 is abundant in adipose tissue and opposes the accumulation of dietary erucic acid (C22:1) in fat." Journal of lipid research 51, 1 (2010): 162-8. [PubMed Link] | [ Full text ]
  • Burke, K.T.;Colvin, P.L.;Myatt, L.;Graf, G.A.;Schroeder, F.;Woollett, L.A. "Transport of maternal cholesterol to the fetus is affected by maternal plasma cholesterol concentrations in the golden Syrian hamster." Journal of lipid research 50, 6 (2009): 1146-55. [PubMed Link] | [ Full text ]
  • Sabeva, N.S.;Liu, J.;Graf, G.A. "The ABCG5 ABCG8 sterol transporter and phytosterols: implications for cardiometabolic disease." Current opinion in endocrinology, diabetes, and obesity 16, 2 (2009): 172-7. [PubMed Link] | [ Full text ]
  • White, J.;Guerin, T.;Swanson, H.;Post, S.;Zhu, H.;Gong, M.;Liu, J.;Everson, W.V.;Li, X.A.;Graf, G.A.;Ballard, H.O.;Ross, S.A.;Smart, E.J. "Diabetic HDL-associated myristic acid inhibits acetylcholine-induced nitric oxide generation by preventing the association of endothelial nitric oxide synthase with calmodulin." American journal of physiology. Cell physiology 294, 1 (2008): C295-305. [PubMed Link] | [ Full text ]
  • Sabeva, N.S.;Rouse, E.J.;Graf, G.A. "Defects in the leptin axis reduce abundance of the ABCG5-ABCG8 sterol transporter in liver." The Journal of biological chemistry 282, 31 (2007): 22397-405. [PubMed Link] | [ Full text ]
  • Zhang, D.W.;Graf, G.A.;Gerard, R.D.;Cohen, J.C.;Hobbs, H.H. "Functional asymmetry of nucleotide-binding domains in ABCG5 and ABCG8." The Journal of biological chemistry 281, 7 (2006): 4507-16. [PubMed Link] | [ Full text ]
  • Graf, G.A.;Cohen, J.C.;Hobbs, H.H. "Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking." The Journal of biological chemistry 279, 23 (2004): 24881-8. [PubMed Link] | [ Full text ]
  • Graf, G.A.;Yu, L.;Li, W.P.;Gerard, R.;Tuma, P.L.;Cohen, J.C.;Hobbs, H.H. "ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion." The Journal of biological chemistry 278, 48 (2003): 48275-82. [PubMed Link] | [ Full text ]
  • Graf, G.A.;Li, W.P.;Gerard, R.D.;Gelissen, I.;White, A.;Cohen, J.C.;Hobbs, H.H. "Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface." The Journal of clinical investigation 110, 5 (2002): 659-69. [PubMed Link] | [ Full text ]
  • Stangl, H.;Graf, G.A.;Yu, L.;Cao, G.;Wyne, K. "Effect of estrogen on scavenger receptor BI expression in the rat." The Journal of endocrinology 175, 3 (2002): 663-72. [PubMed Link] | [ Full text ]
  • Hobbs, H.H.;Graf, G.A.;Yu, L.;Wilund, K.R.;Cohen, J.C. "Genetic defenses against hypercholesterolemia." Cold Spring Harbor symposia on quantitative biology 67, (2002): 499-505. [PubMed Link] | [ Full text ]
  • Graf, G.A.;Roswell, K.L.;Smart, E.J. "17beta-Estradiol promotes the up-regulation of SR-BII in HepG2 cells and in rat livers." Journal of lipid research 42, 9 (2001): 1444-9. [PubMed Link] | [ Full text ]
  • Burns, P.D.;Graf, G.A.;Hayes, S.H.;Silvia, W.J. "Effect of oxytocin on expression of cytosolic phospholipase A2 mRNA and protein in ovine endometrial tissue in vivo." Domestic animal endocrinology 19, 4 (2000): 237-46. [PubMed Link] | [ Full text ]
  • Berge, K.E.;Tian, H.;Graf, G.A.;Yu, L.;Grishin, N.V.;Schultz, J.;Kwiterovich, P.;Shan, B.;Barnes, R.;Hobbs, H.H. "Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters." Science (New York, N.Y.) 290, 5497 (2000): 1771-5. [PubMed Link] | [ Full text ]
  • Graf, G.A.;Matveev, S.V.;Smart, E.J. "Class B scavenger receptors, caveolae and cholesterol homeostasis." Trends in cardiovascular medicine 9, 8 (1999): 221-5. [PubMed Link] | [ Full text ]
  • Smart, E.J.;Graf, G.A.;McNiven, M.A.;Sessa, W.C.;Engelman, J.A.;Scherer, P.E.;Okamoto, T.;Lisanti, M.P. "Caveolins, liquid-ordered domains, and signal transduction." Molecular and cellular biology 19, 11 (1999): 7289-304. [PubMed Link] | [ Full text ]
  • Graf, G.A.;Burns, P.D.;Silvia, W.J. "Expression of a cytosolic phospholipase A2 by ovine endometrium on days 11-14 of a simulated oestrous cycle." Journal of reproduction and fertility 115, 2 (1999): 357-63. [PubMed Link] | [ Full text ]
  • Graf, G.A.;Connell, P.M.;Westhuyzen, D.R.;Smart, E.J. "The class B, type I scavenger receptor promotes the selective uptake of high density lipoprotein cholesterol ethers into caveolae." The Journal of biological chemistry 274, 17 (1999): 12043-8. [PubMed Link] | [ Full text ]
  • Graf, G.A.;Burns, P.D.;Silvia, W.J. "Oxytocin- and aluminium fluoride-induced phospholipase C activity and prostaglandin F2 alpha secretion during the ovine luteolytic period." Journal of reproduction and fertility 112, 2 (1998): 225-31. [PubMed Link] | [ Full text ]
  • Webb, N.R.;Connell, P.M.;Graf, G.A.;Smart, E.J.;Villiers, W.J.;Beer, F.C.;Westhuyzen, D.R. "SR-BII, an isoform of the scavenger receptor BI containing an alternate cytoplasmic tail, mediates lipid transfer between high density lipoprotein and cells." The Journal of biological chemistry 273, 24 (1998): 15241-8. [PubMed Link] | [ Full text ]
  • Burns, P.D.;Graf, G.A.;Hayes, S.H.;Silvia, W.J. "Cellular mechanisms by which oxytocin stimulates uterine PGF2 alpha synthesis in bovine endometrium: roles of phospholipases C and A2." Domestic animal endocrinology 14, 3 (1997): 181-91. [PubMed Link] | [ Full text ]
  • Burns, P.D.;Tsai, S.J.;Wiltbank, M.C.;Hayes, S.H.;Graf, G.A.;Silvia, W.J. "Effect of oxytocin on concentrations of prostaglandin H synthase-2 mRNA in ovine endometrial tissue in vivo." Endocrinology 138, 12 (1997): 5637-40. [PubMed Link] | [ Full text ]