The intake of large amounts of cholesterol in the diet has become one of the main causes of cardiovascular disease, and its related diseases such as atherosclerosis, coronary heart disease and cerebral stroke are also increasingly threatening people's health. Niemann-Pick Type C1-Like 1 (NPC1L1) protein is a key protein that mediates the absorption of dietary cholesterol. The protein interacts with other proteins to form a class of membrane-rich membrane domains that efficiently mediate cholesterol absorption. Although previous studies have revealed the molecular mechanism of NPC1L1 protein-mediated cholesterol absorption to a certain extent, there are still many questions that have not been answered. For example, the function of each domain of the NPC1L1 protein is not clear; the absorption efficiency of cholesterol by the human body is much greater than that of plant sterols, and its molecular mechanism is not yet clear.
On May 20, The Journal of Biological Chemistry published online the latest research results of the research group of Song Baoliang, Institute of Biochemistry and Cell, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, on the N-terminal domain of NPC1L1 protein binding cholesterol and promoting cholesterol absorption. The research work found that the N-terminal domain of NPC1L1 protein directly binds cholesterol, and amino acid mutations such as L216 affect the binding of the protein to cholesterol, which in turn affects the absorption of cholesterol in cells and mouse models.
Further, the ability of the N-terminal domain to bind cholesterol determines the formation of cholesterol-rich membrane domains and the efficiency of cholesterol absorption, explaining the molecular mechanism by which the N-terminal domain promotes cholesterol absorption. Interestingly, the N-terminal domain of NPC1L1 protein does not bind phytosterols, revealing the molecular mechanism of intestinal specific absorption of cholesterol. In this research work, 25-hydroxycholesterol can competitively inhibit the absorption of cholesterol by NPC1L1 protein, and the existing cholesterol absorption inhibitor Ezatamibe acts at another site of NPC1L1 protein, suggesting that the N-terminal domain of NPC1L1 protein can be used as Screening for new cholesterol absorption inhibitor targets.
Song Baoliang's research group has conducted a series of systematic studies on cholesterol absorption. This work further revealed the molecular mechanism of cholesterol absorption mediated by NPC1L1 protein and provided a new strategy for screening cholesterol absorption inhibitors.
This thesis was mainly completed by PhD students Zhang Jinhui and Ge Liang. The research project was funded by the 973 project of the Ministry of Science and Technology, the National Natural Science Foundation of China, the Chinese Academy of Sciences and the Shanghai Municipal Science and Technology Commission.
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