||Researchers at the University
of Pennsylvania School of Medicine have discovered
that a group of liver enzymes called proprotein convertases
(PCs) may be the key to raising levels of good cholesterol
||Several PC enzymes, called furin, PACE4,
and PCSK5A, disable another enzyme called endothelial lipase
by clipping off a piece of it and by activating its inhibitor,
an increased level of HDL-C in the blood.
||The study appears in the current issue
of Cell Metabolism.
(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine have discovered that a group of liver enzymes called proprotein convertases (PCs) may be the key to raising levels
cholesterol (HDL-C). The pathway by which these proteins
are able to achieve an increase in HDL cholesterol involves another
enzyme that normally degrades HDL-C, and was also discovered at
Penn. The newly recognized relationship between these enzymes and
cholesterol represents another target for ultimately controlling
good cholesterol. The study appears in the current issue of Cell
“Several PC enzymes, called furin, PACE4, and PCSK5A, disable
another enzyme called endothelial lipase by clipping off a piece of it
and by activating its inhibitor,” says first author Weijun
Jin, MD, Research Assistant Professor of Pharmacology. “This promotes
an increased level of HDL-C in the blood.”
“We showed that mice engineered to express high levels of PCSK5A
had 50 percent higher HDL-C than control mice,” says senior author
Daniel J. Rader, MD, the Cooper/McLure Professor of Medicine and Associate
Director of the Institute for Translational
Medicine and Therapeutics at Penn.
Increased HDL-C is due to decreased endothelial lipase (EL) activity. “This
is encouraging because it suggests that either the PC or EL enzyme might
be targets for drug therapy to raise good cholesterol, an unmet medical
need in patients with low HDL-C,” says Rader. What’s more,
the increase in HDL-C was shown to promote reverse cholesterol transport,
the process by which HDL protects against heart
Low levels of HDL-C put people at risk for atherosclerosis, thereby
increasing the risk of heart
attack and stroke. Although this study was
performed in mice, humans have the same proprotein convertases and endothelial
lipase, and these enzymes are conserved in all vertebrates. Jin and Rader
expect that the same pathway for controlling HDL-C will apply to humans.
The next step is to study how the genes for the PCs, EL itself, and
EL’s inhibitor are regulated. In addition, Jin and Rader plan to
test whether variation in blood levels of PCs and EL activity in humans,
as well as genetic variation in their genes, is associated with variation
in HDL-C levels and heart disease risk.
“We hope to identify polymorphisms in the genes for PCs, EL, and
its inhibitor that are associated with HDL-C levels, thus supporting
that this pathway is relevant in humans,” says Rader.
Co-authors are Xun Wang, John S. Millar, and Jane M. Glick from Penn
Quertermous (Stanford University) and George
H. Rothblat (Children’s
Hospital of Philadelphia). The study was funded by the National
Heart, Lung, and Blood Institute and the American
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