Insulin signaling molecule, mTORC1, regulates VLDL-triglyceride production which if increases in the blood, could lead to cardiovascular disease, says study.

‘Targeting mTORC1 pharmacologically could decrease the risk of cardiovascular disease that is associated with obesity and diabetes.’

After eating, glucose rises, which induces insulin release to control blood sugar levels by increasing glucose uptake and reducing glucose production by the liver. In addition to glucose regulation, insulin also controls blood lipid levels in part by increasing lipid synthesis, uptake, and storage in fat cells. 




The mTOR complex
In the JCI paper, the team demonstrated that mTOR complex 1 (mTORC1), a protein super-molecule made up of several smaller proteins, is essential for very low density lipoprotein (VLDL)-triglyceride production. VLDL-triglyceride molecules are exported by the liver and carry lipids to peripheral tissues. "This is important because in metabolic diseases associated with insulin resistance the liver makes more triglycerides, which leads to increased levels in the blood and eventually cardiovascular disease," Titchenell said.
In mice, the absence of mTORC1 in liver cells caused a build-up of triglycerides in the liver, thereby reducing circulating triglycerides. On the other hand, activation of mTORC1 depleted liver triglycerides and increased blood triglycerides. Titchenell identified an important cellular process controlled by mTORC1 and demonstrated that mTORC1 controls the production of another class of molecules called phospholipids, which are essential for the triglyceride export from the liver. Phospholipids are necessary to form a barrier around triglyceride molecules allowing for their export and transport throughout the body.
"In insulin-resistant disorders such as diabetes and obesity, hyperactive mTORC1 in liver leads to excess fat production and export," Titchenell said. "mTORC1 is what we want to target pharmacologically to decrease the risk of cardiovascular disease that is associated with obesity and diabetes. If we could affect mTORC1 in a balanced way, then maybe could help prevent non-alcoholic fatty liver disease and heart disease."
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