Journal Article

XBP1 links the 12-hour clock to NAFLD and regulation of membrane fluidity and lipid homeostasis

Zhu, Bokai, Dacso, Clifford C., York, Brian, Lonard, David M., Gonzales, Naomi M., Meng, Huan, Putluri, Nagireddy, O’Malley, Bert W.

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/51 / 38 / 42 / 45 / 45/15 / 45/91 / 59 / 631/337/2019 / 631/337/572 / 631/337/572/2102 / 631/443/319 / Ablation / Activating transcription factor 1 / Animals / Biological clocks / Cell membranes / Cellular stress response / Circadian Clocks / Circadian rhythm / Circadian rhythms / Constraining / Disruption / Fatty acids / Fatty Acids - metabolism / Fatty liver / Fluidity / Gene Expression Regulation / Homeostasis / Humanities and Social Sciences / Humans / Lipids / Liver / Liver - metabolism / Liver - pathology / Liver diseases / Maintenance / Male / Membrane Fluidity / Metabolic disorders / Metabolism / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / multidisciplinary / Non-alcoholic Fatty Liver Disease - genetics / Non-alcoholic Fatty Liver Disease - pathology / Periodicity / Perturbation / Phenotypes / Phospholipid composition / Phospholipids / Phospholipids - metabolism / Science / Science (multidisciplinary) / Transcription / Viscosity / X-Box Binding Protein 1 - genetics / X-Box Binding Protein 1 - metabolism