Gregory Graf, PhD
Connect
859-257-4749Gregory.Graf@uky.edu
Positions
- Professor, Physiology
- Associate Director, Saha Cardiovascular Research Center
College Unit(s)
Other Affiliation(s)
- Nutritional Sciences Graduate Faculty
- CVRC - Core Faculty
Biography and Education
Biography
Dr. Gregory Graf holds a PhD in Physiology from the College of Medicine at the University of Kentucky. Following postdoctoral training in Molecular Genetics in the laboratory of Dr. Helen Hobbs at the UT Southwestern Medical Center in Dallas, he returned to the University of Kentucky and joined the faculty. Dr. Graf was appointed as the Associate Director of the Saha Cardiovascular Research Center in 2022.
The goal of Dr. Graf’s research program is to identify novel proteins and pathways that directly influence risk factors for metabolic diseases that include dyslipidemia, hyperglycemia, insulin resistance, and inflammation. Cholesterol has long been known to increase risk for cardiovascular disease. It is now clear that disturbances in cholesterol metabolism also contribute to obesity-related phenotypes such as insulin resistance, inflammation, and metabolic dysfunction-associated steatotic liver disease (MASLD). Our present focus is to understand the mechanism by which disruptions in sterol homeostasis influence these risk factors and to determine if accelerating cholesterol elimination will improve obesity-related metabolic dysfunction.
Education
PhD: Physiology, University of Kentucky, Lexington, KY
Fellowship: Molecular Genetics, University of Texas Southwestern Medical School at Dallas, TX
Research
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 disease, diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). This triad is collectively termed Cardiometabolic disease.
Cholesterol and triglycerides are largely found in the blood on apolipoprotein B-containing lipoproteins (ApoB-LPs). Elevations in ApoB-LP lipids are associated with the development of Cardiometabolic diseases. The liver and intestine play major roles in the synthesis and secretion of ApoB-LPs as well as their removal from the blood.
ABCG5 and ABCG8 form a cholesterol transporter that is expressed in both the liver and intestine and represents the major route for cholesterol elimination from the body. The absence of this transporter worsens the development of Cardiometabolic disease phenotypes in mouse models of obesity. Our data also suggest 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 and intestine and is protective in Cardiometabolic disease.
A second project focuses on the role of mitochondrial fatty acid metabolism on plasma cholesterol. Genome wide association studies (GWAS) and epigenome wide association studies (EWAS) link the enzyme carnitine palmitoyltransferase 1a (Cpt1a) with plasma levels of lipoprotein cholesterol. Genetic manipulations in mice support a causal relationship between Cpt1a and plasma cholesterol levels. However, the relationship between fatty acid entry into mitochondria and plasma cholesterol is unclear. The goal of this project is to dissect the molecular mechanisms that link mitochondrial metabolism to the regulation of cellular cholesterol levels and the synthesis, secretion and clearance of ApoB-LPs.
Selected Publications
Li, J., S. S. Pijut, Y. Wang, A. Ji, R. Kaur, R. E. Temel, D. R. van der Westhuyzen, and G. A. Graf. 2019. Simultaneous Determination of Biliary and Intestinal Cholesterol Secretion Reveals That CETP (Cholesteryl Ester Transfer Protein) Alters Elimination Route in Mice. Arterioscler Thromb Vasc Biol 39: 1986-1995.
Slade, E., M. R. Irvin, K. Xie, D. K. Arnett, S. A. Claas, T. Kind, D. W. Fardo, and G. A. Graf. 2021. Age and sex are associated with the plasma lipidome: findings from the GOLDN study. Lipids Health Dis 20: 30.
Anspach, G. B., R. Kaur, I. Chauhan, E. L. Savage, B. Poole, V. P. Noffsinger, X. Fu, Z. Wang, C. Voy, R. E. Temel, S. R. Gordon, R. N. Helsley, and G. A. Graf. 2025. ABCG5 ABCG8-independent mechanisms fail to maintain sterol balance in mice fed a high cholesterol diet. J Lipid Res: 100902.
Helsley, R. N., M. M. Zelows, V. P. Noffsinger, G. B. Anspach, N. Dharanipragada, A. E. Mead, I. Cobo, A. Carter, Q. Wu, I. Shalaurova, K. Saito, J. M. Morganti, S. M. Gordon, and G. A. Graf. 2025. Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers ApoB-Containing Lipoproteins in Mice. Arterioscler Thromb Vasc Biol 45: 1368-1388.