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.

Physiology, Molecular Genetics, Cell Biology, Mouse Models Cholesterol Metabolism: Absorption, Transport, & Elimination Regulation of the primary cholesterol elimination transporter, ABCG5 ABCG8 (G5G8)

Pijut S S, Corbett D E, Wang Y, Li J, Charnigo Richard, Graf Gregory A. (2016). Effect of peripheral circadian dysfunction on metabolic disease in response to a diabetogenic diet. American journal of physiology. Endocrinology and metabolism, 310(11), E900-11. Wang Y, Su K, Sabeva N S, Ji A, van der Westhuyzen Deneys Rem, Foufelle F, Gao X, Graf Gregory A. (2015). GRP78 rescues the ABCG5 ABCG8 sterol transporter in db/db mice. Metabolism: clinical and experimental, 64(11), 1435-43. Wang Yi-Tin, Liu X, Pijut S S, Li J, Horn J, Bradford E M, Leggas Markos, Barrett Terrence Anthony, Graf Gregory A. (2015). The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination. Journal of lipid research, Liu X, Liu J, Lester J D, Pijut S S, Graf Gregory A. (2015). ABCD2 identifies a subclass of peroxisomes in mouse adipose tissue. Biochemical and biophysical research communications, 456(1), 129-34. Liu Xiaoxi, Liu Jingjing , Liang Shuang, Schulter Agatha, Fourcade Stephane, Aslibekyan Stella, Pujol Aurora, Graf Gregory A. (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(5), 505-513. Su K, Sabeva N S, Wang Y, Liu X, Lester J D, Liu J, Liang S, Graf Gregory A. (2014). Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice. Arteriosclerosis, thrombosis, and vascular biology, 34(1), 26-33. Meyer J M, Graf Gregory A, van der Westhuyzen Deneys Rem. (2013). New developments in selective cholesteryl ester uptake. Curr Opin Lipidol, 24(5), 386-92. Salous A K, Panchatcharam M, Sunkara M, Mueller P, Dong A, Wang Y , Graf Gregory A, Smyth S S, Morris A J. (2013). Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice. The Journal of Lipid Research, 54(10), 2775-84. Su Kai, Sabeva Nadezhda S, Liu Jingjing, Bhatnagar Saloni, van der Westhuyzen Deneys Rem, Wang Yuhuan, Graf Gregory A. (2012). 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/the American Society for Biochemistry & Molecular Biology, 287, 28564-28575. Liu J, Liang S, Liu X, Brown J A, Newman K E, Sunkara M, Morris Andrew James, Bhatnagar S, Li X, Pujol A, Graf Gregory A. (2012). The absence of ABCD2 sensitizes mice to disruptions in lipid metabolism by dietary erucic acid . J Lipid Res, 53(6), 1071-9.