Principal Investigator Profile - Curriculum Vitae
Name: |
T.Y. (Ta-Yuan) Chang |
Position: |
Professor of Biochemistry |
INSTITUTION AND LOCATION |
DEGREE |
YEAR(s) |
FIELD OF STUDY |
National Taiwan University |
B.S. |
1967 |
Chemistry |
University of North Carolina, Chapel Hill |
Ph.D. |
1973 |
Biochemistry |
Washington University School of Medicine, St. Louis |
Postdoc. |
1973-76 |
Biochemistry |
A. Positions and Honors
Professional Experience
1976-2000 Assistant Professor, Associate Professor, and Professor of Biochemistry, Dartmouth Medical School
2000-2008 Professor and Chair, Biochemistry, Dartmouth Medical School
2000-present Professor, Biochemistry, Dartmouth Medical School
1995-2000 Visiting Professor at Kumamoto University Medical School, Kumamoto, Japan
1995-2006 Member of Editorial Board, Journal of Biological Chemistry
2006-present Member of Editorial Board, Acta Biochimica Biophysica Sinica
1997-2001 American Heart Association National Research Study Committee Member
2005-2009 NIH Integrated Nutrition and Metabolism Study Section Member
2001-2007 Taiwan National Health Research Institute Advisory Committee Member
1982-1987 NIH Research Career Development Award
1994-2004 NIH MERIT Award
B. Summary of the PI's Earlier Scientific Accomplishments
The PI's laboratory isolated and characterized four classes of CHO cell mutants in cholesterol metabolism. These mutant cell lines have been employed by many laboratories for various investigations. Notably, these cell lines have served as tools for the identification of four new genes in cholesterol metabolism: the Acat1 gene (Ref.i), the Scap gene (Ref.ii), the S2p gene (Ref.iii), and the Npc1 gene (Ref.iv). The identification of the Acat1 gene, accomplished in the PI's laboratory, opened the door for molecular studies on the ACAT1 enzyme. It also led other investigators to the identification of related genes involved in neutral lipid biosynthesis, in phospholipid remodeling, and in acylation of the peptide hormone ghrelin which stimulates appetite in the brain.
Ref.ia
Cadigan, K., Heider, J., and Chang, T.Y. Isolation and characterization of Chinese hamster ovary cell mutants deficient in acyl-coenzyme A:cholesterol acyltransferase activity. J. Biol. Chem. 263, 274 (1988)
Ref.ib
Chang, C.C.Y., Huh, H.Y., Cadigan, K. M., and Chang, T.Y. Molecular cloning and functional expression of human acyl-coenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells J. Biol. Chem. 268, 20747 (1993)
Ref.ic
Chang, T.Y. Chang, C.C.Y., and Cheng, D. Acyl-coenzyme A:cholesterol acyltransferase. Annual Rev. Biochemistry 66, 613 (1997)
Ref.iia
Chang, T.Y. and Limanek. Regulation of cytosolic acetoacetyl coenzyme A thiolase, 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and mevalonate kinase by low density ipoprotein and by 25-hydroxycholesterol in Chinese hamster ovary Cells. J. Biol. Chem. 255, 7787 (1980)
Ref.iib
Hua, X., A. Nohturfft, Goldstein, J.L., and Brown, M.S. Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 87, 415. (1996)
Ref.iiia
Hasan, M.T., Chang, C.C.Y., and Chang, T.Y. Somatic cell genetic and biochemical characterization of cell lines resulting from human genomic DNA transfection of Chinese hamster ovary cell mutants defective in sterol-dependent activation of sterol synthesis and LDL receptor expression. Somatic Cell & Mol. Genetics 20, 183 (1994)
Ref.iiib
Rawson, R.B., Zelenski, N.G., Nijhawan, D., Ye, J., Sakai, J., Hasan, M.T., Chang, T.Y., Brown, M.S., and Goldstein, J.L. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Molecular Cell 1, 47 (1997)
Ref.iva
Cadigan, K.M., Spillane, D.M., and Chang, T.Y. Isolation and characterization of Chinese hamster ovary cell mutants defective in intracellular low density lipoprotein-cholesterol trafficking. J. Cell Biol. 110, 295 (1990)
Ref.ivb
Carstea, E.D., Morris, J.A., et al. The Niemann-Pick C gene: homology to mediators of cholesterol homeostasis. Science 277, 228 (1997)
C. Selected Recent Publications (Since 2003)
(corresponding author indicated in bold)
Khan, N., Shen, J., Chang, T.Y., Chang, C.C.Y., Fung, P.C.W., Grinberg, O., Demidenko, E., and Swartz, H. Plasma Membrane Cholesterol: A Possible Barrier to Intracellular Oxygen in Normal and Mutant CHO Cells Defective in Cholesterol Metabolism. Biochemistry 42, 23 (2003)
Zhang, Y., Yu, C., Liu, J., Spencer, T.A., Chang, C.C.Y., and Chang, T.Y. Cholesterol is superior to 7-ketocholesterol or 7alpha-hydroxycholesterol as an allosteric activator for acyl-coenzyme A: cholesterol acyltransferase 1. J. Biol. Chem. 278, 11642 (2003)
Sugii, S., Reid, P.C., Ohgami, N., Shimada, Y., Maue, R.A., Ninomiya, H., Ohno-Iwashita, Y., and Chang, T.Y. Biotinylated theta toxin derivative as a probe to examine intracellular cholesterol-rich domains in normal and Niemann-Pick type C1 cells. J. Lipid Res. 44, 1033 (2003)
Reid, P.C., Sugii, S., and Chang, T.Y. Trafficking defects in endogenously synthesized cholesterol in fibroblasts, macrophages, hepatocytes, and glial cells from NPC1 mice. J. Lipid Res. 44, 1010 (2003)
Lin, S., Lu, X., Chang, C.C.Y., and Chang, T.Y. Human Acyl-Coenzyme A: Cholesterol Acyltransferase 2 (hACAT2) expressed in Chinese hamster ovary cells: membrane topology and active site location. Mol. Biol. Cell. 14, 2447 (2003)
Sugii, S., Reid, P.C., Ohgami, N., Du, H., and Chang, T.Y. Distinct endosomal compartments in early trafficking of low density lipoprotein-derived cholesterol. J. Biol. Chem. 278, 27180 (2003)
Wiegand, V., Chang, T.Y., Strauss, J.F., Fahrenholz, F., and Gimpl, G. Transport of plasma membrane-derived cholesterol and the function of Niemann-Pick C1 protein. FASEB J. 17, 782 (2003)
Sawamura, N., Gong, J.-S., Chang, T.Y., Yanagisawa, K., and Michikawa, M. Promotion of tau phosphorylation by MAP kinase Erk1/2 is accompanied by reduced cholesterol level in detergent-insoluble membrane fraction in Niemann-Pick C1-deficient cells. J. Neurochem. 84, 1086 (2003)
Sakashita, N., Miyazaki, A., Chang, C.C.Y., Chang, T.Y., Kiyota, E., Satoh, M., Komohara, Y., Morganelli, P.M., Horiuchi, S., and Takeya, M. Acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) is induced in monocyte-derived macrophages: in vivo and in vitro studies. Lab Invest. 83, 1569 (2003)
Ohgami, N., Ko, D.C., Thomas, M., Scott, M.P., Chang, C.C.Y., and Chang, T.Y. Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain. Proc. Natl. Acad. Sci. USA 101, 12473 (2004)
Reid P.C., Sakashita N., Sugii S., Ohno-Iwashita Y., Shimada Y., Hickey W.F., and Chang T.Y. A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain. J Lipid Res. 45, 582 (2004)
Yang, L., Yang, J.B., Chen, J., Yu, G.Y., Zhou, P., Lei, L., Wang, Z.Z., Chang, C.C.Y., Yang, X.Y., Chang, T.Y., Li, B.L. Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone. Cell Res. 14, 315 (2004)
Yamauchi, Y., Chang, C.C.Y., Hayashi, M., Abe-Dohmae, S., Reid, P.C., Chang, T.Y., and Yokoyama, S. Intracellular cholesterol mobilization involved in the ABCA1/apolipoprotein-mediated assembly of high density lipoprotein in fibroblasts. J Lipid Res. 45, 1943 (2004)
Yang, L., Lee, O., Chen, J., Chen, J., Chang, C.C.Y., Zhou, P., Wang, Z.Z., Ma, H.H., Sha, H.F., Feng, J.X., Wang, Y., Yang, X.Y., Wang, L., Dong, R., Ornvold, K., Li, B.L., and Chang, T.Y. Human acyl-coenzyme A:cholesterol acyltransferase 1 (acat1) sequences located in two different chromosomes (7 and 1) are required to produce a novel ACAT1 isoenzyme with additional sequence at the N-terminal. J. Biol. Chem. 279, 46253 (2004)
Guo, Z.-Y., Chang, C.C.Y., Lu, X., Chen, J., Li, B.-L., and Chang, T.Y. The disulfide linkage and the free sulfhydryl accessibility of acyl-coenzyme A:cholesterol acyltransferase 1 as studied by using mPEG5000-maleimide. Biochemistry 44, 6537 (2005)
Paul, C., Reid, P.C., Boegle, A., Karten, B., Zheng, M., Lin, L., Chang, T.Y., Vance, J., Blanchette-Mackie, J., Maue, R. Adenovirus expressing an NPC1-GFP fusion gene corrects neuronal and non-neuronal defects associated with Niemann Pick Type C disease. J. Neurosci. Res. 81, 706 (2005)
Liu, J., Chang, C.C., Westover, E.J., Covey, D.F., Chang, T.Y. Investigating the allosterism of Acyl Coenzyme A: cholesterol acyltransferase (ACAT) by using various sterols: In vitro and intact cell studies. Biochem. J. 391, 389 (2005)
Guo, Z.-Y., Lin, S., Heinen, J.A., Chang, C.C.Y., and Chang, T.Y. The active site histidine460 of human acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) residues in a hitherto undisclosed transmembrane domain. J. Biol. Chem. 280, 37814 (2005)
Chang, T.Y., Reid, P.C., Sugii, S., Ohgami, N., Cruz, J.C., and Chang, C.C.Y. The Niemann-Pick type C disease and intracellular cholesterol trafficking. J. Biol. Chem. 280, 20917 (2005) (Review)
Song, B.L., Wang, C.H., Yao, X.M., Yang, L., Zhang, W.J., Wang, Z.Z., Yang, J.B., Qi, W., Yang, X.Y., Inoue, K., Lin, Z.X., Zhang, H.Z., Kodama, T., Chang, C.C., Liu, Y.K., Chang, T.Y., and Li, B.L. Human acyl-CoA: cholesterol acyltransferase 2 gene expression in intestinal Caco-2 cells and in hepatocellular carcinoma. Biochem. J. 394, 617 (2006)
Chang, C., Dong, R., Miyazaki, A., Sakashita, N., Zhang, Y., Liu, J., Guo, M., Li, B.L., and Chang, T.Y. Human acyl-CoA:cholesterol acyltransferase (ACAT) and its potential as a target for pharmaceutical intervention against atherosclerosis. Acta Biochim. Biophys. Sin. 38, 151 (2006) (Review)
Li, B.L., Chang, T.Y., Chen, J., Chang, C.C.Y., and Zhao, X.N. Human ACAT1 gene expression and its involvement in the development of atherosclerosis. Future Medicine (Future Cardiology section), 2, 93 (2006)
Chang, T.Y., Chang, C.C.Y., Ohgami, N., and Yamauchi, Y. Cholesterol Sensing, Trafficking, and Esterification. Ann. Rev. Cell Dev. Biol. 22, 129 (2006) (Review)
Sugii, S., Lin, S., Ohgami, N., Ohashi, M., Chang, C.C.Y., and Chang, T.Y.. Roles of endogenously synthesized sterols in the endocytic pathway. J Biol Chem. 281, 23191 (2006)
Guo, Z.Y., Chang, C.C.Y., and Chang, T.Y.. The functionality of the seventh and eighth transmembrane domains of acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1). Biochemistry 46 , 10063(2007).
Yamauchi Y., Reid P.C., Sperry J.B., Chang, C.C.Y.,and Chang T.Y.. Plasma membrane rafts complete cholesterol synthesis by participating in retrograde movement of precursor sterols. J Biol.Chem. 282, 34994 (2007).
Reid, P.C., Lin, S., Vanier, M.T., Ohno-Iwashita, Y., Harwood, Jr. H.J., Hickey, W.F., Chang, C.C.Y., and Chang, T.Y.. Partial blockage of sterol biosynthesis with a squalene synthase inhibitor in early postnatal Niemann-Pick type C null mice brains reduces neuronal cholesterol accumulation, abrogates astrogliosis, but may inhibit myelin maturation. J. Neurosci.. Methods 168, 15 (2008)
Chen, J., Zhao, X.N., Yang, L., Hu, G.J., Lu, M., Xiong, Y., Yang, X.Y.,Chang, C.C.Y., Song, B.L., Chang, T.Y., and Li, B.L..The RNA secondary structures located at the interchromosomal region of human ACAT1 chimeric mRNA are required to produce the 56-kD isoform. Cell Research 18, 1 (2008)
Chang, T.Y., and Chang, C.C. Y.. Ezetimide blocks the internalization of the NPC1L1/cholesterol complex. Cell Metabolism. 7, 469 (2008) (Preview)
Urano, Y., Watanabe, H., Murphy, S., Shibuya, Y., Geng, Y., Peden, A.A., Chang, C.C.Y., and Chang, T.Y. Transport of LDL-derived cholesterol from the NPC1 compartment to the ER involves the trans-Golgi network and the SNARE protein complex. Proc. Natl. Acad. Sci. USA 105, 16513 (2008)
D.Recent Research Interests in the PI's Laboratory
1. Functional Analysis of ACAT
2. Intracellular Cholesterol Trafficking
3. Cholesterol Metabolism and Neuropathology