Spatiotemporal gating of SIRT1 functions by O-GlcNAcylation is essential for liver metabolic switching and prevents hyperglycemia

Abstract

Inefficient physiological transitions are known to cause metabolic disorders. Therefore, investigating mechanisms that constitute molecular switches in a central metabolic organ like the liver becomes crucial. Specifically, upstream mechanisms that control temporal engagement of transcription factors, which are essential to mediate physiological fed–fast–refed transitions are less understood. SIRT1, a NAD+-dependent deacetylase, is pivotal in regulating hepatic gene expression and has emerged as a key therapeutic target. Despite this, if/how nutrient inputs regulate SIRT1 interactions, stability, and therefore downstream functions are still unknown. Here, we establish nutrient-dependent O-GlcNAcylation of SIRT1, within its N-terminal domain, as a crucial determinant of hepatic functions. Our findings demonstrate that during a fasted-to-refed transition, glycosylation of SIRT1 modulates its interactions with various transcription factors and a nodal cytosolic kinase involved in insulin signaling. Moreover, sustained glycosylation in the fed state causes nuclear exclusion and cytosolic ubiquitin-mediated degradation of SIRT1. This mechanism exerts spatiotemporal control over SIRT1 functions by constituting a previously unknown molecular relay. Of note, loss of SIRT1 glycosylation discomposed these interactions resulting in aberrant gene expression, mitochondrial dysfunctions, and enhanced hepatic gluconeogenesis. Expression of nonglycosylatable SIRT1 in the liver abrogated metabolic flexibility, resulting in systemic insulin resistance, hyperglycemia, and hepatic inflammation, highlighting the physiological costs associated with its overactivation. Conversely, our study also reveals that hyperglycosylation of SIRT1 is associated with aging and high-fat–induced obesity. Thus, we establish that nutrient-dependent glycosylation of SIRT1 is essential to gate its functions and maintain physiological fitness.

Sirt1 coordinates with ERα to regulate autophagy and adiposity

“…Sirtuin 1 (Sirt1) is an energy sensor that regulates metabolism across tissues 14,15 . Activation or overexpression of Sirt1 improves systemic metabolism and protects against diabetes, obesity, or high-fat diet-induced metabolic damages [16][17][18][19][20][21][22] , while dysregulated Sirt1 resulted in phenotypes associated with diabetes, obesity, and aging 23 . In adipocytes, upregulation of Sirt1 enhances lipolysis and attenuates adipogenesis 24 , and ablation of Sirt1 promotes adipocyte differentiation and increases adiposity in mice 25,26 .…”

Continuous variable response, kinetic gating and connectivity that govern IS topology are perturbed in hyperinsulinemia

“…Others and we have found that metabolic cues under fasting conditions elicit anticipatory molecular mechanisms to mount an efficient fed response (Chattopadhyay et al, 2020;Maniyadath et al, 2019;Shaw et al, 2020). Given that fasting insulin (0.1nM) is pulsatile with a frequency of 10-15min, our findings have shown that this rewires fed IS dynamics.…”

Inhaled [D-Ala2]-Dynorphin 1-6 Prevents Hyperacetylation and Release of High Mobility Group Box 1 in a Mouse Model of Acute Lung Injury

“…We have found that leytragin promoted SIRT1 mRNA transcription in the lungs of LPS-induced mice. We did not measure SIRT1 protein levels, since the SIRT1 protein undergoes rapid degradation in the fed state via the ubiquitin-proteasome pathway [ 38 ] (all animals in our study had free access to food over the 72-hour period of observation). Thus, the upregulation of SIRT1 expression appears to be the mechanism by which leytragin shifts the acetylation-deacetylation balance toward HMGB1 deacetylation, thereby preventing HMGB1 release in LPS-induced mice.…”