1. The role of extracellular lipases as important physiologic and pathophysiologic regulators of lipoprotein metabolism and function whose expression is both genetically determined and influenced by inflammatory factors. We have cloned several new members of the lipoprotein lipase gene family and are investigating their function and regulation.
2. Molecular and cellular mechanisms by which HDL-associated proteins inhibit atherogenesis and induce regression of atherosclerotic lesions. Somatic gene transfer of HDL-associated proteins is used in mouse models of Atherosclerosis in order to study their effects on atherogenesis in vivo. Tissue culture models have been developed in order to reconstruct cellular aspects of the atherosclerotic process in vitro and determine anti-inflammatory effects of HDL proteins.
3. Dietary and genetic regulation of hepatic lipoprotein production. Gene transfer, transgenic, and cell culture approaches are used to study the interaction between specific genes, such as the microsomal transfer protein and diacylglycerol acyltransferase, and dietary manipulation in the regulation of hepatic apoB production in mice. Lipoprotein kinetic studies are also performed in humans using endogenous labeling of apolipoproteins with stable isotopically labeled leucine.
4. Genetic factors associated with premature atherosclerotic disease and high or low levels of HDL cholesterol. Subjects with family history of premature coronary disease or with extremes of HDL cholesterol are recruited and phenotyped for cardiovascular risk factors and clinical and subclinical Atherosclerosis. Candidate genes are investigated for their association with subclinical Atherosclerosis or variation in HDL cholesterol levels and linkage analysis of sib pairs and large pedigrees will be performed.
5. Novel therapeutic approaches to lipid disorders and Atherosclerosis. We are involved in translational proof-of-concept studies in animals and humans of novel approaches to raising HDL cholesterol, improving HDL function, and reducing atherogenic lipoproteins. The overall focus of our research effort is basic cell and molecular laboratory science with translation into animal experiments and ultimately into patient-oriented research in the areas of lipoprotein metabolism and premature Atherosclerosis.

Selected Key Publications:

Liu Y, Millar JS, Cromley DA, Graham M, Crooke R, Billheimer JT, Rader DJ. Knockdown of Acyl-CoA:diacylglycerol acyltransferase 2 with antisense oligonucleotide reduces VLDL TG and ApoB secretion in mice. Biochim Biophys Acta. 2008 Mar;1781:97-104.

Millar JS, et al. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism. J Lipid Res. 2008 Mar;49:543-9.

Badellino, KO, Wolfe, ML, Reilly MP, Rader DJ. Endothelial lipase is increased in vivo by inflammation in humans. Circulation. 2008 Feb 5;117:678-85.

Helgadottir A, et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008 Feb;40:217-24.

Ali K, Lund-Katz S, Lawson J, Phillips MC & Rader DJ. Structure-function properties of the apoE-dependent COX-2 pathway in vascular smooth muscle cells. Atherosclerosis 2008 Jan;196(1):201-9.

Tanigawa H, Billheimer JT, Tohyama JI, Zhang Y, Rothblat G, Rader DJ. Expression of Cholesteryl Ester Transfer Protein in Mice Promotes Macrophage Reverse Cholesterol Transport. Circulation 2007 Sep 11;116(11):1267-73.

Jin W, Wang X, Millar JS, Quertermous T, Rothblat GH, Glick JM & Rader DJ. Hepatic proprotein convertases modulate HDL metabolism. Cell Metab 6: 129-136, 2007.

Wang X, Collins HL, Ranalletta M, Fuki IV, Billheimer JT, Rothblat GH, Tall AR & Rader DJ. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest 117: 2216-2224, 2007.

Lebherz C, Sanmiguel J, Wilson JM, Rader DJ. Gene transfer of wild-type apoA-I and apoA-I Milano reduce Atherosclerosis to a similar extent. Cardiovasc Diabetol 6: 15, 2007.

Wang X, Jin W & Rader DJ. Upregulation of macrophage endothelial lipase by toll-like receptors 4 and 3 modulates macrophage interleukin-10 and -12 production. Circ Res 100: 1008-1015, 2007.

Pellizzon MA, Billheimer JT, Bloedon LT, Szapary PO & Rader DJ. Flaxseed reduces plasma cholesterol levels in hypercholesterolemic mouse models. J Am Coll Nutr 26: 66-75, 2007.

Brown RJ, Miller GC, Griffon N, Long CJ & Rader DJ. Glycosylation of endothelial lipase at asparagine-116 reduces activity and the hydrolysis of native lipoproteins in vitro and in vivo. J Lipid Res 48: 1132-1139, 2007.

Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, Millar JS, Ikewaki K, Siegelman ES, Gregg RE & Rader DJ. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 356: 148-156, 2007.

Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest 116: 3090-3100, 2006.

Broedl UC, Jin W, Fuki IV, Millar JS & Rader DJ. Endothelial lipase is less effective at influencing HDL metabolism in vivo in mice expressing apoA-II. J Lipid Res 47: 2191-2197, 2006.

Millar JS, Stone SJ, Tietge UJ, Tow B, Billheimer JT, Wong JS, Hamilton RL, Farese RV Jr, Rader DJ. Short-term overexpression of DGAT1 or DGAT2 increases hepatic triglyceride but not VLDL triglyceride or apoB production. J Lipid Res 47: 2297-2305, 2006.

Kitajima K, Marchadier DH, Miller GC, Gao GP, Wilson JM & Rader DJ. Complete prevention of Atherosclerosis in apoE-deficient mice by hepatic human apoE gene transfer with adeno-associated virus serotypes 7 and 8. Arterioscler Thromb Vasc Biol 26: 1852-1857, 2006.

Griffon N, Budreck EC, Long CJ, Broedl UC, Marchadier DH, Glick JM & Rader DJ. Substrate specificity of lipoprotein lipase and endothelial lipase: studies of lid chimeras. J Lipid Res 47: 1803-1811, 2006.

Millar JS, Brousseau ME, Diffenderfer MR, Barrett PH, Welty FK, Faruqi A, Wolfe ML, Nartsupha C, Digenio AG, Mancuso JP, Dolnikowski GG, Schaefer EJ & Rader DJ. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans. Arterioscler Thromb Vasc Biol 26: 1350.1356, 2006.

Kitajima K, Marchadier DH, Burstein H &Rader DJ. Persistent liver expression of murine apoA-l using vectors based on adeno-associated viral vectors serotypes 5 and 1. Atherosclerosis 186: 65-73, 2006.

Samaha FF, Szapary PO, Iqbal N, Williams MM, Bloedon LT, Kochar A, Wolfe ML & Rader DJ. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome. Arterioscler Thromb Vasc Biol 26: 624-630, 2006.

Badellino KO, Wolfe ML, Reilly MP & Rader DJ. Endothelial lipase concentrations are increased in metabolic syndrome and associated with coronary Atherosclerosis. PLoS Med 3: e22, 2006.

Naik SU, Wang X, Da Silva JS, Jaye M, Macphee CH, Reilly MP, Billheimer JT, Rothblat GH & Rader DJ. Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation 113: 90-97, 2006.

Szapary PO, Bloedon LT, Samaha FF, Duffy D, Wolfe ML, Soffer D, Reilly MP, Chittams J & Rader DJ. Effects of Pioglitazone on Lipoproteins, Inflammatory Markers, and Adipokines in Nondiabetic Patients with Metabolic Syndrome. Arterio Thromb Vasc Biol 26: 182-188, 2006.

Cain WJ, Millar JS, Himebauch AS, Tietge UJ, Maugeais C, Usher D & Rader DJ. Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]. J Lipid Res 46: 2681-2691, 2005.

Jin W, Fuki IV, Seidah NG, Benjannet S, Glick JM & Rader DJ. Proprotein convertases [corrected] are responsible for proteolysis and inactivation of endothelial lipase. J Biol Chem 2005 Nov 4;280(44):36551-9. Erratum in: J Biol Chem 280: 41124, 2005.

Ali K, Middleton M, Puré E & Rader DJ. Apolipoprotein E suppresses the type I inflammatory response in vivo. Circ Res 97: 922-927, 2005.

Moore RE, Navab M, Millar JS, Zimetti F, Hama S, Rothblat GH & Rader DJ. Increased Atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation. Circ Res 97: 763-771, 2005.

Zhang Y, Da Silva JR, Reilly M, Billheimer JT, Rothblat GH & Rader DJ. Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo. J Clin Invest 115: 2870-2874, 2005.

Brousseau ME, Diffenderfer MR, Millar JS, Nartsupha C, Asztalos BF, Welty FK, Wolfe ML, Rudling M, Bjorkhem I, Angelin B, Mancuso JP, Digenio AG, Rader DJ & Schaefer EJ. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol 25: 1057-1064, 2005.

Millar JS, Maugeais C, Ikewaki K, Kolansky DM, Barrett PH, Budreck EC, Boston RC, Tada N, Mochizuki S, Defesche JC, Wilson JM & Rader DJ. Complete deficiency of the low-density lipoprotein receptor is associated with increased apolipoprotein B-100 production. Arterioscler Thromb Vasc Biol 25: 560-565, 2005.

Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA & Rader DJ. Resistin is an inflammatory marker of Atherosclerosis in humans. Circulation 111: 932-939, 2005.

Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP & Rader DJ. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 350: 1505-1515, 2004.

Zhang Y, Zanotti I, Reilly M, Glick JM, Rothblat GH & Rader DJ. Overexpression of apoA-I promotes reverse transport of cholesterol from macrophages to feces. Circulation 108: 661-663, 2003.

Szapary PO, Wolfe ML, Bloedon LT, Cucchiaria AJ, DerMarderosian AH, Cirigliano MD, Rader DJ. Guggulipid for the treatment of hypercholesterolemia: a randomized, controlled trial. JAMA 290: 765-772, 2003.

Jin W, Millar JS, Broedl U, Glick JM & Rader DJ. Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo. J Clin Invest 111: 357-362, 2003.