Meng Huan, Gonzales Naomi M, Lonard David M, Putluri Nagireddy, Zhu Bokai, Dacso Clifford C, York Brian, O'Malley Bert W
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Nat Commun. 2020 Dec 4;11(1):6215. doi: 10.1038/s41467-020-20028-z.
A distinct 12-hour clock exists in addition to the 24-hour circadian clock to coordinate metabolic and stress rhythms. Here, we show that liver-specific ablation of X-box binding protein 1 (XBP1) disrupts the hepatic 12-hour clock and promotes spontaneous non-alcoholic fatty liver disease (NAFLD). We show that hepatic XBP1 predominantly regulates the 12-hour rhythmicity of gene transcription in the mouse liver and demonstrate that perturbation of the 12-hour clock, but not the core circadian clock, is associated with the onset and progression of this NAFLD phenotype. Mechanistically, we provide evidence that the spliced form of XBP1 (XBP1s) binds to the hepatic 12-hour cistrome to directly regulate the 12-hour clock, with a periodicity paralleling the harmonic activation of the 12-hour oscillatory transcription of many rate-limiting metabolic genes known to have perturbations in human metabolic disease. Functionally, we show that Xbp1 ablation significantly reduces cellular membrane fluidity and impairs lipid homeostasis via rate-limiting metabolic processes in fatty acid monounsaturated and phospholipid remodeling pathways. These findings reveal that genetic disruption of the hepatic 12-hour clock links to the onset and progression of NAFLD development via transcriptional regulator XBP1, and demonstrate a role for XBP1 and the 12-hour clock in the modulation of phospholipid composition and the maintenance of lipid homeostasis.
除了24小时的昼夜节律钟外，还存在一个独特的12小时时钟来协调代谢和应激节律。在此，我们表明肝脏特异性敲除X盒结合蛋白1（XBP1）会破坏肝脏的12小时时钟，并促进自发性非酒精性脂肪性肝病（NAFLD）。我们表明，肝脏中的XBP1主要调节小鼠肝脏中基因转录的12小时节律性，并证明12小时时钟的紊乱而非核心昼夜节律钟的紊乱与这种NAFLD表型的发生和进展有关。从机制上讲，我们提供的证据表明，XBP1的剪接形式（XBP1s）与肝脏的12小时顺反组结合，直接调节12小时时钟，其周期性与许多已知在人类代谢疾病中受到干扰的限速代谢基因的12小时振荡转录的谐波激活平行。在功能上，我们表明Xbp1敲除显著降低细胞膜流动性，并通过脂肪酸单不饱和和磷脂重塑途径中的限速代谢过程损害脂质稳态。这些发现揭示，肝脏12小时时钟的基因破坏通过转录调节因子XBP1与NAFLD发展的发生和进展相关，并证明XBP1和12小时时钟在调节磷脂组成和维持脂质稳态中的作用。
