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Accumulation of cholesteryl
esters as cytoplasmic lipid droplets within cells
of human aortic tissue is a characteristic feature of early lesions of
atherosclerotic plaque. These cholesteryl esters are produced through biochemical
reaction catalyzed by the enzyme acyl coenzyme A:cholesterol acyltransferase (ACAT).
In intestines of vertebrate animals, including human, the extent of
absorption of dietary cholesterol can be shown to be significantly reduced by
inhibiting intestinal ACAT activity.
In livers of vertebrate animals, formation of
lipoproteins require proper supply of cholesteryl
esters produced through ACAT reaction.
For these reasons, many pharmaceutical companies in the United States
and abroad are in the process of developing specific chemical reagents to
inhibit ACAT activity for the purpose of therapeutic prevention/treatment of
human hypercholesterolemia and human atherosclerosis. ACAT is a membrane-bound enzyme located in
the endoplasmic reticulum of various tissues of animal and human cells. It has never been purified to homogeneity
while still retaining biological activity.
The protein structure as well as its amino acid composition or amino
acid sequence of ACAT is at present unknown.
The structure of genomic DNA or the nucleotide sequence of cDNA encoding the ACAT gene has never been reported in
literature.
Dartmouth researchers cloned a new human cDNA (K1) which, when ligated
with mammalian expression vector (pcDNA1) and transfected into mammalian cells, expresses
human-specific acyl coenzyme A:cholesterol acyltransferase
(ACAT) activity in intact cells and in cell-free extracts. In particular, a stable transfectant
clone (14e)
has been shown to express high levels of human ACAT activity assayed by
various means. This invention thus
enables the investigators to use K1 cDNA or any
derivative of this cDNA to express large amounts of
human ACAT activity in intact mammalian cells and in various cell-free
systems for the purpose of screening and testing for chemical agents serving
as specific ACAT inhibitors to be developed for therapeutic prevention/treatment of
hypercholesterolemia, human atherosclerosis, and other diseases arising from
high cholesterol levels.
This clone is covered by Dartmouth’s issued
Untied States Patent No. 5,484,727.
The entire ACAT gene, isolated, cloned, and sequenced in Dartmouth laboratories
is covered in the issued United States Patent No. 5,834,283. The utility of these materials is claimed
in the issued United States Patent No. 5,968,749. We are seeking an industrial partner to
further refine and market this technology. (Ref: J4)
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