TRPV1调控肠道胆固醇转运的分子机制研究

Reducing intestinal cholesterol absorption and lowering blood cholesterol level is the primary means of early prevention of atherosclerosis (AS). NPC1L1 of intestinal epithelial cell brush border is responsible for cholesterol uptake, adenosine triphosphate binding cassette transporters ABCG5/G8 are responsible for cholesterol efflux, and which are regulated by LXR. In our previous work, we confirmed the mechanism of activation of TRPV1 inhibited foam cell formation by regulating cholesterol transporting of vascular smooth muscle cells, and proved that TRPV1 agonist, capsaicin, may lower the cholesterol level of mice. So, we suppose that TRPV1 regulates intestinal epithelial cells NPC1L1 and ABCG5/G8 functions, inhibits intestinal cholesterol absorption, and lower blood cholesterol level. To confirm this hypothesis, we intend to use TRPV1-/ - mice and Caco-2 cell line, observe intestinal epithelial cell cholesterol transporters NPC1L1 and ABCG5/G8 to clarify the molecular mechanism of dietary capsaicin induced TRPV1 activation regulates intestinal epithelial cells cholesterol absorption. We changed our research concern from the previous on TRPV1 reducing muscle-derived foam cell formation to the direct regulation of intestinal lipid transport, and forwarded AS prevention and treatment targets from cardiovascular to intestine. Our project will provide a theoretical basis for primary prevention of AS.

减少肠道胆固醇吸收及降低血胆固醇水平是早期防治动脉粥样硬化(AS)的主要手段。肠上皮细胞NPC1L1负责胆固醇摄取， ABCG5/G8负责胆固醇流出，且受LXR转录水平调节。前期工作中我们证实激动辣椒素受体TRPV1调节血管平滑肌细胞胆固醇转运抑制泡沫细胞形成的机制，且TRPV1激动剂辣椒素具有降低小鼠血浆总胆固醇的作用。故我们设想激动TRPV1调节肠上皮细胞NPC1L1和ABCG5/G8功能，抑制肠道胆固醇吸收，降低血胆固醇水平。为证实上述假设，我们拟利用TRPV1-/-小鼠和Caco-2细胞，紧扣肠上皮细胞胆固醇转运子NPC1L1和ABCG5/G8，观察激动TRPV1调控肠上皮细胞胆固醇转运的机制。我们的研究视角从既往关注激动TRPV1减少肌源性泡沫细胞形成前移到直接调控肠道脂质转运，将AS防治靶点从心血管前移到肠道，为AS一级预防提供新策略。

减少肠道胆固醇吸收及降低血胆固醇水平是早期防治动脉粥样硬化(AS)的主要手段。肠上皮细胞NPC1L1 负责胆固醇摄取， ABCG5/G8 负责胆固醇流出，且受LXR 转录水平调节。既往我们证实激动辣椒素受体TRPV1 调节血管平滑肌细胞胆固醇转运抑制泡沫细胞形成的机制，且TRPV1 激动剂辣椒素具有降低小鼠血浆总胆固醇的作用。故我们设想激动TRPV1 调节肠上皮细胞NPC1L1 和ABCG5/G8功能，抑制肠道胆固醇吸收，降低血胆固醇水平。本项课题研究中，我们利用TRPV1-/-小鼠和Caco-2 细胞，证明辣椒素干预可减弱高脂饮食引起的胆固醇水平合成增加、抑制肠道胆固醇吸收；高脂饮食后小鼠肠管的收缩和舒张功能减退，辣椒素干预后可改善肠管的舒缩功能；辣椒素长期干预后野生小鼠肠管PKA、LXR蛋白表达减弱、ABCG5/8蛋白表达明显增加、ACAT2表达下降，但在TRPV1基因敲除小鼠无上述作用，提示辣椒素通过TRPV1刺激肠道上皮细胞胆固醇向细胞外转运，减弱肠道上皮细胞的胆固醇酯化作用。总之，本研究证实膳食辣椒素干预为AS一级预防提供新策略。