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

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

doi:10.1038/s41467-020-20028-z

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.

Highlights

A distinct 12-hour clock exists in addition to the 24-hour circadian clock to coordinate metabolic and stress rhythms
We have extended our characterization of X-box binding protein 1 (XBP1) as a molecular component of the 12-h clock[4], showing that XBP1 plays a key role in controlling membrane fluidity and its ability to properly maintain phospholipid composition and lipid homeostasis, linking the 12-h clock to the onset and progression of a type of non-alcoholic fatty liver disease (NAFLD) development via XBP1s transcriptional regulation
We noted that previous studies focusing on spontaneous XBP1 function were conducted in young mice at 3–4 months of age, and none of these earlier animal studies monitoring hepatic steatosis were aware of the robust 12-h clock rhythmicity that exists in the endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways[27,28]

Summary

Introduction

A distinct 12-hour clock exists in addition to the 24-hour circadian clock to coordinate metabolic and stress rhythms. We show that Xbp[1] 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. With 12-h periodic rhythmicity, X-box binding protein 1 (XBP1s) has been shown to regulate many ER homeostatic and rate-limiting metabolic genes that control glycolysis, fatty acid oxidation, and oxidative phosphorylation[1,3,4] Both the mRNA and protein levels of XBP1s display robust 12-h oscillations in the mouse liver that are cell-autonomous and independent of the master circadian clock regulator BMAL1 or external circadian cues[2,3,4]. These findings suggest that the XBP1-dependent 12-h clock is important for the liver to maintain healthy metabolic homeostasis

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Results

Conclusion