During the past few years, we have
worked on two general areas, the pathogenesis of
hypertriglyceridemia and diseases of the nuclear lamina.
Our group discovered a GPI-anchored
endothelial cell protein, GPIHBP1, that is critically important for
the lipoprotein lipase–mediated processing of triglyceride-rich
lipoproteins. Mutations in GPIHPB1 in mice and humans cause severe
hypertriglyceridemia. Over the next few years, we intend to focus on
the cell biology of GPIHPB1 and define the precise role of GPIHPB1
regulating plasma triglyceride levels.
We have also sought to define the in
vivo importance of lipid modifications of proteins. Much of this
work has been focused on the nuclear lamins, which are
posttranslationally modified by a cholesterol biosynthetic
intermediate. The nuclear lamins are building blocks for the nuclear
lamina—a structural scaffolding for the cell nucleus. Defects in the
posttranslational processing of one of the nuclear lamins (lamin A)
is associated with a devastating pediatric genetic disease, progeria.
We proposed that abnormal posttranslational processing of the
nuclear lamins might contribute to the pathogenesis of disease, and
we further hypothesized that drugs that interfere with the
posttranslational processing pathway might improve disease
phenotypes. At least in the mouse, our hypothesis proved to be
Over the next few years, our laboratory
will work to define the in vivo importance of the B-type lamins,
lamin B1 and lamin B2.
Our laboratory works on specific
molecules, and we make use of diverse techniques in molecular and
cellular biology. We are also experts in the creation of genetically
modified mouse models, and when appropriate, we make use of mouse
models to address our research questions.
Weinstein MM, Yin L, Beigneux AP, Davies
BS, Gin P, Estrada K, Melford K, Bishop JR, Esko JD, Dallinga-Thie
GM, Fong LG, Bensadoun A, Young SG. (2008) Abnormal patterns of
lipoprotein lipase release into the plasma in GPIHPB1-deficient
mice, J. Biol. Chem., 12, 34511–34518.
Beigneux AP, Davies BS, Gin P, Weinstein
MM, Farber E, Qiao X, Peale F, Bunting S, Walzem RL, Wong JS, Blaner
WS, Ding ZM, Melford K, Wongsiriroj N, Shu X, de Sauvage F, Ryan RO,
Fong LG, Bensadoun A, Young SG. (2007) Glycosylphosphatidylinositol-anchored
high-density lipoprotein-binding protein 1 plays a critical role in
the lipolytic processing of chylomicrons. Cell Metabolism, 5,
Coffinier C, Hudon SE, Farber EA, Chang
SY, Hrycyna CA, Young SG, Fong LG. (2007) HIV protease inhibitors
block the zinc metalloproteinase ZMPSTE24 and lead to an
accumulation of prelamin A in cells. Proc. Natl. Acad. Sci. USA,
Yang SH, Andres DA, Spielmann HP,
Young SG, and Fong LG., Progerin elicits disease phenotypes of
progeria in mice whether or not it is farnesylated. J. Clin.
Invest., 2008, 118, 3291-3300.
Gin P, Yin L, Davies BSJ, Weinstein MM,
Ryan RO, Bensadoun A, Fong LG, Young SG, and Beigneux AP, The
acidic domain of GPIHBP1 is important for the binding of lipoprotein
lipase and chylomicrons, J Biol. Chem. 2008, 283, 29554-29562.
Brandon S. J. Davies, Anne P. Beigneux,
Richard H. Barnes II, Yiping Tu, Peter Gin, Michael M. Weinstein,
Chika Nobumori, Rakel Nyrén, Ira Goldberg, Gunilla Olivecrona, André
Bensadoun, Stephen G. Young, Lipase into Capillaries. Cell
Metabolism 2010; In Press:
Coffinier C, Chang SY, Nobumori C,
Farber EA, Toth J, Fong LG, and Young SG. Abnormal
Development of the Cerebral Cortex and Cerebellum in the Setting of
Lamin B2 Defiency.. Proc.Natl.Acad.Sci 2010; (107): 5076-5081.
Lee R, Chang SY, Trinh H, White AC,
Bergo MO, Fong LG, Lowry WE, and Young SG. Genetic Analysis
of the Importance of the Protein Prenyltransferases in Skin
Keratinocytes. Human Molecular Gen. 2009; (19): 1603-1617.
Coffinier C, Jung HJ, Li Z, Nobumori C,
Yun UJ, Farber EA, Davies BS, Weinstein MM, Yang SH, Lammerding J,
Farahani JN, Bentolila LA, Fong LG, Young SG. Direct
Synthesis of Lamin A, Bypassing Prelamin A Processing, Causes
Misshapen Nuclei in Fibroblasts but No Detectable Pathology in Mice.
J Biol Chem 2010; (May 3):
Davies BS, Barnes RH 2nd, Tu Y, Ren S,
Andres DA, Spielmann HP, Lammerding J, Wang Y, Young SG, Fong
LG. An Accumulation of Non-Farnesylated Prelamin A Causes
Cardiomyopathy but Not Progeria.. Hum Mol Genet. 2010; (May4):
Beigneux AP, Gin P, Davies BS, Weinstein
MM, Bensadoun A, Fong LG, Young SG. Highly Conserved
Cysteines within the Ly6 domain of GPIHBP1 are Crucial for the
Binding of Lipoprotein Lipase: J. Biol. Chem. 2009; (284): 30240 -
Weinstein MM, Yin L, Tu Y, Wang X, Wu X,
Castellani LW, Walzem RL, Lusis AL, Fong LG, Beigneux AP, Young
SG. Chylomicronemia Elicits Atherosclerosis in Mice.
Arterioscler Thromb Vasc Biol. 2010; (30): 20-23.
Beigneux AP, Franssen R, Bensadoun A,
Gin P, Melford K, Peter J, Walzem RL, Weinstein MM, Davies BS,
Kuivenhoven JA, Kastelein JJ, Fong LG, Dallinga-Thie GM, Young SG.
Chylomicronemia with a Mutant GPIHBP1 (Q115P) that Cannot Bind
Lipoprotein Lipase. . Arterioscler Thromb Vasc Biol. 2009; (29):