Potential therapeutic target for clogged arteries
It is known that cardiovascular disease arises mainly as a result of lipids from the blood plasma that are deposited in the walls of blood vessels, which ultimately restricts blood flow. This complex and deadly disease is believed to affect about a third of the world's population. It is critically important to advance the knowledge and understanding of the mechanisms that regulate the levels of blood lipids. Studies have shown that fat molecules that are also called lipids, for example, cholesterol and triglycerides move back and forth around the circulatory system. This shuttling of fat molecules is caused by a protein called Apolipoprotein-B (ApoB). Further, researchers have named these complexes of lipid and protein as ApoB-containing lipoproteins. These proteins are essential for transporting lipids from the intestine and liver to the tissues of the body. However, since they can also cause cardiovascular disease, they are known as bad cholesterol.
In a new research, researchers in the US reported a protein critical for the synthesis of ApoB-containing lipoproteins. This protein, called MTP, or microsomal triglyceride transfer protein, is shown to be highly conserved in animals, from insects to humans. Researchers have shown that MTP loads lipids onto ApoB, a key initial step in the synthesis of ApoB-containing lipoproteins. Their study was published in PLOS Genetics (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).
From previous studies, it is known that MTP can transfer different types of lipids to ApoB, including triglycerides. They correspond to a major source of energy. These phospholipids are known as the building-blocks of membranes in the cell. In their study, researchers revealed that a mutation in MTP blocks the loading of triglycerides, but it does not block phospholipids onto ApoB. The separation of these two transfer functions was observed for the first time and was unexpected. This finding is important since high triglyceride levels in lipoproteins are correlated with bad clinical condition, which results in diseases such as diabetes and heart disease.
Other identified mutations in MTP preventing both transfer functions of the protein have been reported that can cause a malabsorption syndrome. This makes the intestines to have difficulty absorbing fats and fat-soluble vitamins from the diet, which can result in gastrointestinal distress or more serious problems, such as malnutrition or severe weight loss. However, in this new study that employed zebrafish using the newly identified mutation did not exhibit malabsorption or growth defects. It was attributed to the ability to transfer phospholipids to make ApoB-containing lipoproteins.
MTP has been an important subject of research for its possible role as potential therapeutic target to help lower triglyceride levels in the blood and prevent cardiovascular disease. But, it could not meet the desired goals due to the fact that the existing chemical inhibitors of MTP were proven to be effective and block all MTP function. Such blocking can cause intestinal fat malabsorption and a dangerous accumulation of fat in the liver. This new study paves the way for breakthroughs in the design of more specific MTP inhibitors that can mimic new mutation and selectively block triglyceride transfer to ApoB. The data presented in this study suggests that this type of inhibitor could potentially reduce circulating triglyceride levels without affecting intestine and liver.