Previously unknown regulator of fat and cholesterol production discovered in mice

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Dual role of molecule may open new avenue to cholesterol reduction

Researchers have discovered an unknown regulator of fat and
cholesterol production in the liver of mice, a significant finding that
could eventually lead to new therapies for lowering unhealthy blood levels of
cholesterol and fats.

The team led by scientists from the Harvard School of Public Health
(HSPH) showed how this might work in an animal model, demonstrating
that turning off the regulatory molecule — known as XBP1 — dramatically
reduced blood levels of cholesterol and triglyceride fats. Importantly,
there were no apparent adverse effects on the liver.

Therefore, “XBP1 may be an attractive drug target for treating dyslipidemias [excess fats in the blood],” said Laurie Glimcher,
professor of immunology in the Department of Immunology and Infectious
at HSPH. She is senior author of the report in the journal Science. She said she and her colleagues are
working with collaborators at the Broad Institute of MIT and Harvard to
explore strategies for inhibiting XBP1 activity that could be
applicable to humans.

“A key finding is that the liver in the mice lacking XBP1 seems to
be perfectly normal, with minor effect on normal protein synthesis,”
Glimcher added. “It is a very selective effect in lowering cholesterol
and triglyceride production.”

The researchers discovered that XBP1, a transcription factor that
governs gene expression, is activated by the ingestion of a high
carbohydrate diet. XBP1 then turns on genes for enzymes that cause the
liver to manufacture fat and fat-like substances, which are transported
in the blood to fat tissue for storage. Excess amounts of these
compounds — cholesterol and triglycerides — in the bloodstream can be
dangerous, leading to heart disease and increased risk of strokes.

The discovery of XBP1’s role in manufacturing fats was a surprise to
Glimcher and her co-workers, who include Ann-Hwee Lee, research
scientist at HSPH, Erez Scapa, PhD, and David Cohen. Lee is
first author of the publication. Scapa and Cohen are affiliated with
Harvard Medical School and Brigham and Women’s Hospital.

The molecule had been discovered by Glimcher two decades ago when
she was searching for regulators of genes in the Major
Histocompatiblity Complex
, or MHC, a group of proteins that enables the
immune system to distinguish between “self” and foreign substances in
the body.

More recently, she and others characterized the function of XBP1 as
a coordinator of an emergency response that cells use to survive when
they are threatened by the stress of misfolded proteins. The survival
strategy is known as the Unfolded Protein Response, or UPR. In
addition, XBP1 is required for the normal development of the fetus,
including the liver, and mice lacking XBP1 do not survive to birth.

So what is the role of XBP1 in the adult liver, the scientists
wondered. Lee and colleagues developed a mouse model in which XBP1
functioned normally during fetal development but could be inactivated
at will in the adult. To their surprise, the researchers found that
knocking out XBP1 in adult rodents had no obvious abnormalities — nor
was there any evidence of damage to the liver.

What they did observe, however, was a dramatic decrease of
cholesterol, triglycerides and free fatty acids in the XBP1-knockout
mice compared with normal controls. Moreover, the lack of XBP1 almost
entirely eliminated the “bad” LDL cholesterol in the bloodstream.
Concerned that the triglycerides might be accumulating in the liver
instead — a condition in humans called “fatty liver” — the researchers
found this was not the case, indicating that the manufacture of
triglycerides in the liver was shut down.

When individuals eat excess carbohydrates, their bodies convert
surplus carbohydrates into triglycerides to store them in fat tissue,
which may be used as an energy source when food intake is limited. This
lipid synthesis process occurs in the liver and is dynamically
controlled depending on nutritional condition. XBP1, activated by a
high-carbohydrate diet that strongly promotes lipid synthesis in the
liver, induces several critical enzymes governing this process.

The Glimcher team concluded that XBP1 has a distinct role in
generating lipids in the liver when stimulated by a high-carbohydrate
diet and that this role is not connected in any way with its function
as a regulator of the unfolded protein response. Because XBP1 acts in
such a selective way on the liver’s lipid-making mechanism, the
researchers are eager to determine whether drugs targeted to the
molecule have a future in treating individuals with high blood levels
of triglycerides and cholesterol.

Elevated levels of triglycerides and LDL cholesterol are key
features of metabolic syndrome, which confers high risk of type 2
diabetes and atherosclerosis. The widely used drugs known as statins
reduce blood cholesterol by inhibiting a key enzyme for its synthesis
in the liver; they lower the risk of atherosclerosis. It appears that
XBP1 controls the biosynthesis pathways for both triglycerides and
cholesterol. The researchers hope that compounds that block the XBP1
pathway could lower both triglycerides and cholesterol and thereby help
prevent diabetes and atherosclerosis.

“We don’t yet know whether blocking the XBP1 pathway will be better
than the statins, which are very good drugs but have side effects like
all drugs do,” Glimcher said. “But it is a different pathway.”

This study was supported by the National Institutes of Health and an Ellison Medical Foundation grant.