Newly discovered mutation could point to heart disease therapeutic
target

Date:
August 7, 2020
Source:
Carnegie Institution for Science
Summary:
New work identifies a potential therapeutic target for clogged
arteries and other health risks that stem from an excess of harmful
fats in the bloodstream. The study opens the door for the design
of more specific MTP inhibitors that could reduce circulating
triglyceride levels without the risk of unpleasant and serious
side effects in the intestines and liver.



FULL STORY ==========================================================================
New work led by Carnegie's Meredith Wilson and Steve Farber identifies
a potential therapeutic target for clogged arteries and other health
risks that stem from an excess of harmful fats in the bloodstream. Their findings are published by PLOS Genetics.


========================================================================== "Cardiovascular disease occurs when lipids from the blood plasma are
deposited in the walls of blood vessels, ultimately restricting blood
flow," explained Farber, who specializes in elucidating how cells
process lipids. "This complex disease affects about a third of the
world's population, so improving our understanding of the mechanisms
that regulate the levels of blood lipids has important public health implications." Fat molecules, also called lipids, such as cholesterol
and triglycerides are shuttled around the circulatory system by a protein called Apolipoprotein-B, or ApoB for short. These complexes of lipid
and protein are called ApoB-containing lipoproteins and are essential
for transporting lipids from the intestine and liver to the tissues of
the body. However, because they can also cause cardiovascular disease,
they are commonly known as "bad cholesterol." In this new research,
Wilson, Farber and their colleagues -- including Carnegie's Aidan
Danoff, Monica Hensley, Vanessa Quinlivan, James Thierer and Frederick
Tan -- focused on a protein that is critical for the synthesis of ApoB-containing lipoproteins. This protein, called MTP, or microsomal triglyceride transfer protein, is highly conserved in animals, from
insects to humans. MTP loads lipids onto ApoB, a key initial step in
the synthesis of ApoB-containing lipoproteins.

Normally, MTP can transfer different types of lipids to ApoB, including triglycerides, which are a major source of energy, and phospholipids,
the building-blocks of membranes in the cell. However, the researchers
revealed for the first time a mutation in MTP that blocks the loading
of triglycerides, but not phospholipids, onto ApoB.

"The separation of these two transfer functions was unexpected and
is important, because high triglyceride levels in lipoproteins are
correlated with bad clinical outcomes like diabetes and heart disease,"
said lead author Wilson.

Previously identified mutations in MTP that prevent both transfer
functions of the protein cause a malabsorption syndrome, in which the intestines have difficulty absorbing fats and fat-soluble vitamins from
the diet. This can result in gastrointestinal distress or more serious problems, such as malnutrition or severe weight loss. However, zebrafish
with this newly identified mutation do not exhibit malabsorption or
growth defects, because they can still transfer phospholipids to make ApoB-containing lipoproteins.

For years, MTP has been considered a possible therapeutic target to
help lower triglyceride levels in the blood and prevent cardiovascular
disease. However, the existing chemical inhibitors of MTP are too
effective and block all MTP function, which can cause intestinal fat malabsorption and a dangerous accumulation of fat in the liver.

"Our study opens the door for the design of more specific MTP inhibitors
that mimic this new mutation and selectively block triglyceride
transfer to ApoB," concluded Wilson. "Our data suggests that this type
of inhibitor could reduce circulating triglyceride levels without the
risk of unpleasant and serious side effects in the intestine and liver."

========================================================================== Story Source: Materials provided by
Carnegie_Institution_for_Science. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Meredith H. Wilson, Sujith Rajan, Aidan Danoff, Richard J. White,
Monica
R. Hensley, Vanessa H. Quinlivan, Rosario Recacha, James
H. Thierer, Frederick J. Tan, Elisabeth M. Busch-Nentwich, Lloyd
Ruddock, M. Mahmood Hussain, Steven A. Farber. A point mutation
decouples the lipid transfer activities of microsomal triglyceride
transfer protein. PLOS Genetics, 2020; 16 (8): e1008941 DOI:
10.1371/journal.pgen.1008941 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200807131910.htm

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