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