Health
Research identifies potential therapeutic targets for blocked arteries
A new study led by Carnegie’s Meredith Wilson and Steve Faber has identified potential therapeutic goals for arterial blockage and other health risks due to excess excess fat in the bloodstream. Their findings are PLOS genetics..
“Cardiac vascular disease occurs when lipids from plasma deposit on the walls of blood vessels and ultimately restrict blood flow,” says Farber, specializing in understanding how cells process lipids. is. “Since this complex disease affects about one third of the world’s population, a better understanding of the mechanisms that regulate blood lipid levels has important public health implications.”
Fat molecules, also called lipids such as cholesterol and triglycerides, travel around the circulatory system by a protein called apolipoprotein B, or ApoB for short. These lipid-protein complexes, called ApoB-containing lipoproteins, are essential for transporting lipids from the intestine and liver to body tissues. However, they are commonly known as “bad cholesterol” because they can cause cardiovascular disease.
In this new study, Wilson, Faber, and colleagues at Carnegie’s Aidan Danoff, Monica Hensley, Vanessa Kin Rivan, James Steeler, Frederick Tan, and others focused on proteins important in 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 into ApoB, an important first step in the synthesis of lipoproteins including ApoB.
MTPs can normally transfer different types of lipids to ApoB, including triglycerides, which are the main energy source, and phospholipids, which are components of intracellular membranes. However, researchers have for the first time revealed a mutation in MTP that blocks triglyceride, but not phospholipid, loading on ApoB.
The separation of these two transfer functions is unexpected and important. High triglyceride levels of lipoproteins correlate with poor clinical outcomes such as diabetes and heart disease. “
Meredith Wilson, Lead Author
A previously identified mutation in MTP that interferes with both protein transduction functions causes a malabsorption syndrome in which the intestine has difficulty absorbing fat and fat-soluble vitamins from the diet. This can cause gastrointestinal distress or more serious problems such as malnutrition or severe weight loss. However, zebrafish with this newly identified mutation do not show malabsorption or growth defects. This is because phospholipids can be transferred to make ApoB-containing lipoproteins.
Over the years, MTP has been considered a potential therapeutic target that lowers blood triglyceride levels and may help prevent cardiovascular disease. However, existing chemical inhibitors of MTP are too effective and block all MTP function. This can lead to malabsorption of intestinal fat and a dangerous accumulation of fat in the liver.
“Our work opens the door to the design of more specific MTP inhibitors that mimic this new mutation and selectively block triglyceride transfer to ApoB,” Wilson concluded. .. “Our data suggests that this type of inhibitor can reduce circulating triglyceride levels in the intestine and liver without the risk of unpleasant and serious side effects.”
Source:
See journal:
Wilson, MH, other The (2020) point mutation separates the translipid transfer activity of microsomal triglyceride transfer protein. PLOS genetics. doi.org/10.1371/journal.pgen.1008941..
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