Although it didn't get quite as
much attention as last week's discovery of the source
of the Nile, UBC researchers' unexpected finding that
the intestine is one of the body's main sources of 'good'
high-density lipid cholesterol (HDL-C) certainly has
scientists excited. It was already known the liver was
involved, but the intestine's role came as a bit of
a surprise. The researchers now know that together the
intestine and liver combined churn out 90% of the body's
HDL-C. Their study is featured on the cover of the April
issue of the Journal of Clinical Investigation.
A good modern statin can lower
'bad' low-density lipid cholesterol (LDL-C) by half.
But all efforts to reliably increase the good kind of
cholesterol have essentially failed. Now, a completely
new approach to lipid therapy could be on the horizon
with this new discovery.
"Raising HDL-C is difficult to
do," said Dr Michael Hayden, PhD, one of the study authors
and director of UBC's Centre for Molecular Medicine.
"There's no drug on the market that can raise HDL predictably,
so this is an important target for influencing HDL in
humans."
AN
UNUSUAL SUSPECT
Dr Hayden and his team locally knocked out ABCA1 genes
in mice and measured the effect on HDL-C levels. By
suppressing the gene in the liver, the researchers were
able to prove that some of the cholesterol was still
coming from another source. They nailed that source
by creating mice lacking ABCA1 in the intestine instead
— these mice had HDL-C levels about 30% lower than
normal. "We've shown that HDL is directly secreted from
the gastrointestinal tract," said Dr Hayden. "It continues
the evolving story of ABCA1, this crucial regulator
of HDL-C, and its role in various organs."
It's not news that ABCA1 plays
a critical role in the creation of HDL-C. People who
suffer from Tangier disease, a homozygous dysfunction
of ABCA1, have almost no HDL-C and are extremely prone
to heart disease. But ABCA1 is found in many organs
and adding the intestine's contribution makes up the
numbers. More importantly it offers a potential new
route for therapy: more ABCA1 in the intestine should
theoretically increase HDL-C levels. "I think it's feasible,"
said Dr Hayden. "There are ways of upregulating ABCA1,
and it's an important approach to raising HDL."
Dr Hayden noted that even people
with normal ABCA1 could see their HDL-C levels increase.
"In both those whose activity is a little bit down,
and those with normal ABCA1, any upregulation should
elevate HDL levels," he said. "Variations in ABCA1 are
present in about 10-15% of the population and are associated
with significant variation in risk for heart disease,"
he added. His team is now looking for ways to increase
ABCA1 in the intestine, including dietary approaches.
|
