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

Abstract

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.

Defining the mammalian coactivation of hepatic 12-h clock and lipid metabolism

“…One major mechanism of 12-h clock regulation involves the cycling of genes that have important roles in lipid homeostasis (Meng et al, 2020). To further define the 12-h clock lipidome, Figure 2.…”

“…Chronobiological rhythms govern biological processes and activities that are essential for maintaining physiological homeostasis, enabling organisms to anticipate environmental and nutritional changes for survival. Apart from the well-characterized 24-h circadian clock, an ultradian 12-h periodic rhythmicity is conserved in multiple species ( Cretenet et al, 2010 ; Hughes et al, 2009 ; Meng et al, 2020 ; Pan et al, 2020 ; Zhang et al, 2013 ; Zhu et al, 2017 ). For example, marine organisms possess dominant ~12-h behaviors that can anticipate circatidal nutritional changes in the external environment ( Zhang et al, 2013 ).…”

Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis

“…In contrast to earlier hypothesis that these 12-hour rhythms are under the combined regulation of the 24-hour circadian clock and feeding/fasting cues (2,3), our group identified a cell-autonomous mammalian 12-hour ultradian oscillator that regulates 12-hour rhythms of systemic gene expression and metabolism (4). The 12-hour oscillator is independent from the 24-hour circadian clock but instead is regulated by the unfolded protein response (UPR) transcription factor spliced form of X-Box Binding Protein 1 (XBP1s) (4)(5)(6)(7). In mouse, the liver-specific deletion of XBP1s impaired more than 80% of 12-hour transcriptome, while leaving the majority of circadian transcriptome intact (including all known core circadian clock genes) (5,6).…”

“…In mouse, the liver-specific deletion of XBP1s impaired more than 80% of 12-hour transcriptome, while leaving the majority of circadian transcriptome intact (including all known core circadian clock genes) ( 5 , 6 ). As a result of the 12-hour clock ablation, XBP1s liver-specific knockout (XBP1 LKO ) mice exhibited markedly accelerated liver aging and fatty liver diseases ( 5 ).…”

Circadian Organelles: Rhythms at All Scales

“…These rhythms persist in animals housed in constant dark and that are food-deprived, suggesting that they are endogenously driven [ 103 ]. In fact, XBP1 was recently further shown to regulate 12 h rhythmicity that goes beyond the UPR [ 104 , 105 , 106 ].…”