0156 Both Circadian Clock And Sleep Control Plasma Levels Of Pcsk9, The Main Regulator Of Plasma Ldl Cholesterol. (12th April 2019)

• Record Type: Journal Article
• Authors: Butler, Matthew P; Thosar, Saurabh S; Tavori, Hagai; Rueger, Melanie; Barr, David A; Miles, Joshua R; Fazio, Sergio S; Shea, Steven A
• Is Part Of: Sleep. Volume 42(2019)Supplement 1
• Page Start: A64
• Page End: A65
• Publication Date: 2019-04-12
• Subjects: Sleep -- Physiological aspects -- Periodicals; Sleep disorders -- Periodicals; Sommeil -- Aspect physiologique -- Périodiques; Sommeil, Troubles du -- Périodiques; Sleep disorders; Sleep -- Physiological aspects; Sleep -- physiological aspects; Sleep Wake Disorders; Psychophysiology; Electronic journals; Periodicals; 616.8498
• DOI: 10.1093/sleep/zsz067.155
• Languages: English
• ISSNs: 0161-8105

Abstract

Abstract: Introduction: Shift work is a risk factor for elevated plasma levels of low-density lipoprotein cholesterol (LDL-C); yet the underlying mechanisms remain unclear. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulatory protein synthesized mainly by the liver; PCSK9 causes the degradation of the hepatic LDL receptor and thus, increases plasma LDL-C levels. Under normal physiologic conditions PCSK9 concentration in humans peaks in mid-morning. To determine the mechanisms involved in the dynamic regulation of PCSK9 in humans, we separately tested how the circadian clock and sleep affect circulating PCSK9. Methods: To reveal any endogenous circadian rhythm in PCSK9, 10 healthy participants completed a week-long forced desynchrony (FD) protocol consisting of recurring 20-h "days." Core body temperature was used as the circadian phase marker. To further determine the contribution of sleep versus that of the inactivity that accompanies sleep on PCSK9, 10 additional healthy participants were studied across two nights: one with sleep and one with maintained wakefulness (randomized order). Plasma PCSK9 was measured every ~1.5 h in both protocols. Data were analyzed using mixed model analyses. Results: In the FD, PCSK9 levels follow a strong circadian rhythm, with a peak at ~10:30 AM (~20% change trough to peak, p<0.001). Additionally, PCSK9 levels increased during recurring sleep opportunities (~10% increase), independently of circadian phase (p<0.001). In the second protocol, we further discovered that PCSK9 increased significantly only during sleep (~10% increase, p=0.006) but not during maintained wakefulness and inactivity (p = 0.37). Conclusion: Both the endogenous circadian system and nocturnal sleep contribute to high levels of circulating PCSK9 in the morning. This regulation ties sleep and the circadian clock to the physiological regulation of PCSK9, and will have relevance for LDL-C regulation in shift workers or other conditions of circadian disruption or disrupted sleep. These findings increase our understanding of the physiological regulation of cholesterol homeostasis in healthy individuals and may also have relevance to patients with hypercholesterolemia. Support (If Any): NASA-NNX10AR10G, NIH R01-132985, and Oregon Institute of Occupational Health Sciences, and Knight Cardiovascular Institute.