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David C. Usher, Ph.D.
*Course web site available through MyCourses
Our lab is interested in cholesterol homeostasis in adipocytes (fat cells). The regulation of cholesterol plays a major role in the production of fat droplets in these cells, where it is an essential component of the lipid droplets surface. Thus cholesterol may directly regulate the size of the adipocyte, which is an important factor in obesity. The focus our lab is on the control of cholesterol efflux and the control triglyceride synthesis by a purported transcription factor, SPOT14, which is itself indirectly sensitive to cholesterol levels.
We discovered that Apolipoprotein C-I (apoC-I) is highly up-regulated during the differentiation of both human and mouse adipocytes and that it is controlled by LXR, a transcription factor which is sensitive to a product of cholesterol synthesis. It is controlled in a manner which is similar to apolipoprotein E and the cholesterol transporter ABCA1. This suggests that apoC-I is involved in cholesterol efflux. In addition a second cholesterol transporter, ABCG1, was discovered to be synthesized by mouse but not human adipocytes upon differentiation. Our research is trying to determine the individual roles played by apoC-I, apoE, ABCA1 and ABCG1 in cholesterol efflux from adipocytes.
We are also investigating the function of SPOT14 in adipocytes. Like the cholesterol efflux genes, SPOT14 synthesis is sensitive to control by LXR. However, some of its purported liver target genes are not sensitive to SPOT14 regulation in adipocytes. In addition SPOT14 regulation of the purported genes is different in human and mouse adipocyte cell lines. We are in the process of determining which genes in the metabolism of glucose to triglycerides are regulated by SPOT14 in adipocytes.
- Determining the role of apoC-I in cholesterol efflux. This project involves determining the fate of the apoC-I synthesized by adipocytes, which class of HDL has affinity for the secreted protein, and whether apoC-I itself interacts with either ABCA1 or ABCG1.
- Determining factors which regulate apoC-I synthesis. This project involves the production of various promoter/reporter constructs and their stimulation or suppression by various factors.
- Identifying genes which are sensitive to regulation by SPOT14 and then identifying elements in their promoters which are responsible for this regulation.
- William Cain, Ph.D. - Assistant Professor (Ph.D., University of Delaware). Catabolism of Lp(a).
- Marysol Lavander, B.S. - Graduate Student (B.S., University of Delaware). The role of SPOT14 in the regulation of triglyceride production.
- Aivi Nguyen - Undergraduate. The role of cholesterol efflux in adipocytes.
- Rappaport EB, Usher DC. Obesity, insulin resistance, and type 2 diabetes in children and adolescents. Pediatr Ann. 2006;35(11):822–826.
- Cain WJ, Millar JS, Himebauch AS, et al. Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]. J Lipid Res. 2005;46(12):2681–2691.
- Ikewaki K, Cain W, Thomas F, et al. Abnormal in vivo metabolism of apoB-containing lipoproteins in human apoE deficiency. J Lipid Res. 2004;45(7):1302–1311.
- Cain W, Song L, Stephens G, Usher D. Characterization of lipoproteins from the turtle, Trachemys scripta elegans, in fasted and fed states. Comp Biochem Physiol A Mol Integr Physiol. 2003;134(4):783–794.
- Caird J, Burke M, Roberts G, et al. Apolipoprotein(A) expression in intracranial aneurysms. Neurosurgery. 2003;52(4):854–8; discussion 858–9.
- Rodriguez A, Usher DC. Anti-atherogenic effects of the acyl-CoA:cholesterol acyltransferase inhibitor, avasimibe (CI-1011), in cultured primary human macrophages. Atherosclerosis. 2002;161(1):45–54.
- Ye SQ, Lavoie T, Usher DC, Zhang LQ. Microarray, SAGE and their applications to cardiovascular diseases. Cell Res. 2002;12(2):105–115.
- Ye SQ, Usher DC, Zhang LQ. Gene expression profiling of human diseases by serial analysis of gene expression. J Biomed Sci. 2002;9(5):384–394.
- Fu L, Jamieson DG, Usher DC, Lavi E. Gene expression of apolipoprotein(a) within the wall of human aorta and carotid arteries. Atherosclerosis. 2001;158(2):303–311.
- Jamieson DG, Fu L, Usher DC, Lavi E. Detection of lipoprotein(a) in intraparenchymal cerebral vessels: correlation with vascular pathology and clinical history. Exp Mol Pathol. 2001;71(2):99–105.
- Kawashiri M, Zhang Y, Usher D, Reilly M, Pure E, Rader DJ. Effects of coexpression of the LDL receptor and apoE on cholesterol metabolism and atherosclerosis in LDL receptor-deficient mice. J Lipid Res. 2001;42(6):943–950.
- Snyder PJ, Peachey H, Berlin JA, et al. Effect of transdermal testosterone treatment on serum lipid and apolipoprotein levels in men more than 65 years of age. Am J Med. 2001;111(4):255–260.
- Tangirala RK, Pratico D, FitzGerald GA, et al. Reduction of isoprostanes and regression of advanced atherosclerosis by apolipoprotein E. J Biol Chem. 2001;276(1):261–266.
Phone: (302) 831-6685
Fax: (302) 831-2281
Office: 223 McKinly Lab
Department of Biological Sciences
University of Delaware
Newark, DE 19716
- B.S. - University of California, Irvine
- Ph.D. - University of Iowa
- Postdoctoral - University of Illinois Medical Center