Gregory Graf, PhD

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 nonalcoholic fatty liver disease. 

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 reduce plasma levels of LDL or “bad cholesterol” to reduce the risk of 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 indicates that elevated cholesterol in the liver promotes insulin resistance, inflammation, and 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.  The absence of this transporter worsens the development of fatty liver disease and acutely increasing its levels can restore some aspects of liver function in a mouse model of obesity and fatty liver disease.  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 such that therapeutics can be developed to accelerate cholesterol elimination in the treatment of both cardiovascular and liver 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 these two pathways.