Ezetimibe Blocks Cholesterol Endocytosis

Lipid researchers have identified the mechanism used by the cholesterol-lowering drug ezetimibe to prevent take-up of cholesterol from the diet.

Investigators at the Shanghai Institutes for Biological Sciences (China) based their study on previous findings showing that ezetimibe worked by inhibiting the cholesterol transport protein NPC1L1 (Niemann-Pick C1-like 1).

In the current study, they showed that NPC1L1 physically carries cholesterol into intestinal or liver cells through a process of endocytosis requiring microfilaments and the clathrin/AP2 complex. Blocking NPC1L1, endocytosis dramatically decreased cholesterol internalization, and ezetimibe accomplished this task by preventing NPC1L1 from incorporating into clathrin-coated vesicles. Further data linking ezetimibe to NPC1L1 was presented in the June 4, 2008, issue of the journal Cell Metabolism. The investigators reported that a line of mice genetically engineered to lack NPC1L1 were no longer susceptible to the action of ezetimibe.

"This is a breakthrough in terms of understanding how cholesterol is absorbed,” said senior author Dr. Bao-Liang Song, a researcher at the 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. Therefore, there is an urgent need for more cholesterol uptake inhibitory drugs. Our work provides the molecular basis for developing additional cholesterol absorption inhibitors. Moreover, the cell-based assay that we have established can potentially be used to screen for novel inhibitors of NPC1L1 endocytosis, which will block cholesterol uptake eventually.”


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Shanghai Institutes for Biological Sciences