Pterostilbene modulates diurnal acetylation in mouse liver to ameliorate sleep restriction induced metabolic disorders via restoring circadian-dependent SIRTs activity

Sleep restriction (SR) poses a significant risk for metabolic disorder, correlating to perturb circadian clock. Lysine protein post-translational modifications (PTMs), reversibly modified by the acyltransferases and deacetylases, are identified to regulate metabolic processes in a circadian-dependent manner. Pterostilbene (PTE), a stilbene analogue to resveratrol, had been primarily proved to mitigate metabolic disorders. Thus, it is meaningful to understand how lysine PTMs affected metabolism under SR condition and elucidate the underlying mechanisms of PTE in PTMs perspective. Herein, we firstly revealed that PTE improved systemic energy homeostasis, liver metabolic and mitochondria function of mice subjected to 5-days’ SR in a diurnal range. Then, we primarily screened out that acetylation was the remarkable alteration among the 11 types of lysine PTMs in the livers from SR mice at ZT4 and ZT16. With further LC-MS/MS-based acetylome analysis, 4880 acetylation sites on 1370 proteins were identified, and nearly 50% differentially expressed Kac-modified proteins (DEAPs) were located in the mitochondria. Subsequent analysis demonstrated that PTE could mitigate SR-induced diurnal acetylation disruption of functional proteins related to metabolism, with notably relieving SR-induced inhibition in “amino acid metabolism” and “lipid metabolism” at ZT4. Moreover, PTE could normalize the diurnal expression and activity of deacetylases SIRT1/3 by maintaining NAD⁺ oscillation thus modulating acetylation. Our work represents a comprehensive resource detailing the acetylation modification responded by the liver in sleep deficiency, and provides substantial evidence to illustrate the mechanisms of PTE on SR-induced metabolic disorders.