A gut-derived hormone regulates cholesterol metabolism
A gut-derived hormone regulates cholesterol metabolism
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DOI：
10.1016/j.cell.2024.02.024
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发表时间：
2024-03
期刊：
影响因子：
64.5
通讯作者：
Xiaoli Hu;Fengyi Chen;Liangjie Jia;Aijun Long;Ying Peng;Xu Li;Junfeng Huang;Xueyun Wei
中科院分区：
文献类型：
--
作者：
Xiaoli Hu;Fengyi Chen;Liangjie Jia;Aijun Long;Ying Peng;Xu Li;Junfeng Huang;Xueyun Wei
胆固醇在肠内的吸收和在肝脏中的新胆固醇合成之间的相互协调对于维持胆固醇稳态是必不可少的，然而对这些过程的相反调节的机制仍然知之甚少。在这里，我们确定了一种激素，胆固醇，这是能够抑制胆固醇在肝脏中的合成，导致循环胆固醇水平降低。胆固醇是由一个基因编码的，该基因具有以前未知的功能（人类中的C7 orf 50; Rikin小鼠3110082 I17）。它响应胆固醇吸收而从肠道分泌，并结合GPR 146，GPR 146是一种孤儿G蛋白偶联受体，通过抑制PKA信号传导发挥拮抗下游作用，从而抑制肝脏中SREBP 2控制的胆固醇合成。因此，我们的研究结果表明，胆固醇-GPR 146轴介导的肠道胆固醇吸收对肝脏胆固醇合成的抑制作用。这种发现的激素，胆固醇，有望作为一种有效的药物，在打击高胆固醇血症和动脉粥样硬化。
The reciprocal coordination between cholesterol absorption in the intestine andde novocholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50in humans;3110082I17Rikin mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.