PDF(Pubmed)
Abstract：
Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.
摘要：
氧化固醇是调节胆固醇稳态的胆固醇代谢产物。其中,最丰富的氧固醇是27-羟基胆固醇（27HC），可以穿过血脑屏障。因为27HC作为内源性选择性雌激素受体调节剂，我们假设27HC与大脑中的雌激素受体α（ERα）结合以调节能量平衡。支持这一观点,我们发现，将27HC递送到大脑减少了食物摄入量，并以ERα依赖性方式激活了下丘脑弓状核（POMCARH）中的前黑皮质素（POMC）神经元。此外,我们观察到抑制大脑ERα，删除POMC神经元中的ERα，或对POMCARH神经元的化学遗传抑制阻断了27HC的厌食作用。机械上,我们进一步揭示了27HC通过抑制钙激活钾（SK）通道的小电导来刺激POMCARH神经元。一起,我们的研究结果表明27HC，通过它与ERα的相互作用和SK信道的调制，抑制食物摄入，作为一种负反馈机制，防止循环胆固醇激增。
