A new study in the June issue of Cell Metabolism, a Cell Press publication, sheds light on the action of the drug ezetimibe (trade name Zetia), which is used to treat high cholesterol. Ezetimibe is unique among cholesterol-lowering drugs in that it works by cutting the amount of cholesterol taken in from the diet rather than by blocking cholesterol's manufacture in the body.
Earlier studies had suggested that ezetimibe acts on an intestinal and liver protein recently found to play a critical role in cholesterol absorption. Now, the researchers reveal how that protein known as Niemann-Pick C1-like 1 (NPC1L1) carries cholesterol into the cell. They also show that ezetimibe bars NPC1L1's entry into the cell, thereby keeping cholesterol at bay.
" This is a breakthrough in terms of understanding how cholesterol is absorbed," said Bao-Liang Song of Shanghai Institutes for Biological Sciences. "Now we see how NPC1L1 is recycled between the cell surface and vesicles [inside the cell] and how it takes in cholesterol."
The findings might also have important implications for the search for new cholesterol absorption inhibitors, he added. "If we can uncover the players, we can try to identify new small molecules to interfere with the process."
Despite its bad reputation as a major risk factor for coronary heart disease, cholesterol is an essential component of most biological membranes and is the precursor for synthesis of steroid hormones and bile acids produced by the liver to break down fat. Almost every kind of mammalian cell can synthesize cholesterol, but the process is an energy-intensive one. Therefore, mammals including humans obtain significant amounts of cholesterol from their diets.