Alsehli Ahmed M, Liao Sifang, Al-Sabri Mohamed H, Vasionis Lukas, Purohit Archana, Behare Neha, Clemensson Laura E, Williams Michael J, Schiöth Helgi B
Department of Neuroscience, Functional Pharmacology Unit, Uppsala Biomedical Center (BMC), Uppsala University, Husargatan 3, Box 593, 75124 Uppsala, Sweden.
Faculty of Medicine, King Abdulaziz University and Hospital, Al Ehtifalat St., Jeddah 21589, Saudi Arabia.
Pharmaceuticals (Basel). 2022 Jan 10;15(1):79. doi: 10.3390/ph15010079.
Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode duration. We localized the (PI), equivalent to the mammalian hypothalamus, as the region within the fly brain requiring Hmgcr activity for proper sleep maintenance. Lack of expression in the PI insulin-producing cells recapitulates the sleep effects of pan-neuronal knockdown. Conversely, loss of in a different PI subpopulation, the corticotropin releasing factor (CRF) homologue-expressing neurons (DH44 neurons), increases sleep latency and decreases sleep duration. The requirement for Hmgcr activity in different neurons signifies its importance in sleep regulation. Interestingly, loss of in the PI does not affect circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock. Taken together, these findings suggest that Hmgcr activity in the PI is essential for proper sleep homeostasis in flies.
他汀类药物，即HMG辅酶A还原酶（HMGCR）抑制剂，是用于降低高胆固醇血症和心血管事件风险的一线治疗药物。虽然睡眠障碍被认为是他汀类药物治疗的副作用，但他汀类药物对睡眠的影响仍存在争议。利用果蝇，我们发现了Hmgcr在睡眠调节中的新作用。泛神经元表达缺失会影响果蝇的睡眠行为，导致睡眠潜伏期缩短和睡眠片段持续时间增加。我们将果蝇大脑中相当于哺乳动物下丘脑的脑间部（PI）定位为维持正常睡眠所需Hmgcr活性的区域。PI中胰岛素产生细胞缺乏该蛋白表达会重现泛神经元基因敲低的睡眠效应。相反，在PI的另一个亚群，即表达促肾上腺皮质激素释放因子（CRF）同源物的神经元（DH44神经元）中缺失该蛋白，则会增加睡眠潜伏期并缩短睡眠时间。不同神经元对Hmgcr活性的需求表明其在睡眠调节中的重要性。有趣的是，PI中该蛋白缺失并不影响昼夜节律，这表明Hmgcr通过不同于昼夜节律钟的途径调节睡眠。综上所述，这些发现表明PI中的Hmgcr活性对于果蝇正常的睡眠稳态至关重要。
