Gregory Graf, Ph.D.
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.
We have two main areas of research. The first of these projects focuses on 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. However, little is known about what regulates the activity of this cholesterol “pump”. The goal of this project is to determine how this pump is regulated 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 that fat, or adipose tissue, plays in the development of obesity-related metabolic disorders. Adipose tissue was once thought to simply be a storage organ, but work over the last decade has demonstrated that it plays a pivotal role in the development of insulin resistance, systemic inflammation and increased risk of cardiovascular disease and Type 2 diabetes. Using a unique model of rapid-onset obesity and insulin resistance, we conducted experiments to evaluate changes in gene expression in adipose tissue. The two major pathways disrupted in this model are involved in the regulation of biological rhythms and in lung development. These results suggest that the adipose tissue of obese mice is asynchronous with the rest of the body and that fat cells may undergo genetic reprogramming during the development of adipose dysfunction. Experiments are ongoing to determine if these pathways are casual bystanders during the development of adipose dysfunction or play a causative role. If the latter is true, these pathways will be explored further to determine if therapeutics that target these pathways would be useful in the treatment of obesity-related metabolic diseases.
- 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)
- 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 (PMID: 17561514)
- J Liu, NS Sabeva, S Bhatnagar, X Li, A Pujol and GA Graf 2010 ABCD2 is abundant in adipose tissue and opposes the accumulation of dietary erucic acid (C22:1) in fat The Journal of Lipid Research 51:162-8 (PMID: 19556607)
- 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)
- S 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)
- 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)
- 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)