XBP1 links the 12-hour clock to NAFLD and regulation of membrane fluidity and lipid homeostasis.
XBP1 links the 12-hour clock to NAFLD and regulation of membrane fluidity and lipid homeostasis.
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DOI：
10.1038/s41467-020-20028-z
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发表时间：
2020-12-04
影响因子：
16.6
通讯作者：
O'Malley BW
中科院分区：
文献类型：
--
作者：
Meng H;Gonzales NM;Lonard DM;Putluri N;Zhu B;Dacso CC;York B;O'Malley BW
除了24小时生物钟之外，还有一个独特的12小时生物钟来协调新陈代谢和压力节律。在这里，我们表明，肝脏特异性的X-box结合蛋白1(XBP1)消融扰乱了肝脏的12小时生物钟，并促进了自发性非酒精性脂肪性肝病(NAFLD)的发生。我们发现，肝脏XBP1主要调节小鼠肝脏基因转录的12小时节律性，并证明12小时时钟的扰动，而不是核心生物钟的扰动，与这种NAFLD表型的发生和发展有关。从机制上讲，我们提供的证据表明，XBP1(XBP1s)的剪接形式与肝脏12小时周期结合，直接调节12小时时钟，其周期性与许多已知在人类代谢性疾病中有扰动的限速代谢基因12小时振荡转录的谐波激活平行。在功能上，我们发现XBP1通过在脂肪酸单不饱和和磷脂重塑途径中的限速代谢过程显著降低细胞膜流动性和破坏脂质动态平衡。这些发现表明，肝脏12小时时钟的遗传破坏通过转录调节因子XBP1与NAFLD的发生和发展有关，并表明XBP1和12小时时钟在调节磷脂组成和维持脂质平衡方面发挥了作用。肝细胞12小时节律在细胞应激和代谢功能中起作用。在这里，作者证明了通过删除XBP1来扰乱12小时时钟与NAFLD的发展以及磷脂组成的破坏和维持脂质稳态有关。
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. Hepatocyte 12-hour rhythms have a role in cellular stress and metabolic functions. Here, the authors demonstrate disrupting the 12-hour clock through deletion of XBP1 is associated with the development of NAFLD as well as disruption of phospholipid composition and the maintenance of lipid homeostasis.
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影响因子：
16.6
作者：
Back SH;Kaufman RJ
通讯作者：
Kaufman RJ
影响因子：
19
作者：
Ackerman, Daniel;Simon, M. Celeste
通讯作者：
Simon, M. Celeste
影响因子：
4.7
作者：
Hayashi, M;Morikawa, T;Hori, T
通讯作者：
Hori, T
DOI：
10.1037/h0081810
发表时间：
1975-01-01
期刊：
CANADIAN PSYCHOLOGICAL REVIEW-PSYCHOLOGIE CANADIENNE
影响因子：
--
作者：
BROUGHTON, R
通讯作者：
BROUGHTON, R
影响因子：
64.8
作者：
Chen, Xi;Iliopoulos, Dimitrios;Zhang, Qing;Tang, Qianzi;Greenblatt, Matthew B.;Hatziapostolou, Maria;Lim, Elgene;Tam, Wai Leong;Ni, Min;Chen, Yiwen;Mai, Junhua;Shen, Haifa;Hu, Dorothy Z.;Adoro, Stanley;Hu, Bella;Song, Minkyung;Tan, Chen;Landis, Melissa D.;Ferrari, Mauro;Shin, Sandra J.;Brown, Myles;Chang, Jenny C.;Liu, X. Shirley;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.