Sirtuins Link Inflammation and Metabolism

Abstract

Sirtuins (SIRT), first discovered in yeast as NAD+ dependent epigenetic and metabolic regulators, have comparable activities in human physiology and disease. Mounting evidence supports that the seven-member mammalian sirtuin family (SIRT1-7) guard homeostasis by sensing bioenergy needs and responding by making alterations in the cell nutrients. Sirtuins play a critical role in restoring homeostasis during stress responses. Inflammation is designed to "defend and mend" against the invading organisms. Emerging evidence supports that metabolism and bioenergy reprogramming direct the sequential course of inflammation; failure of homeostasis retrieval results in many chronic and acute inflammatory diseases. Anabolic glycolysis quickly induced (compared to oxidative phosphorylation) for ROS and ATP generation is needed for immune activation to "defend" against invading microorganisms. Lipolysis/fatty acid oxidation, essential for cellular protection/hibernation and cell survival in order to "mend," leads to immune repression. Acute/chronic inflammations are linked to altered glycolysis and fatty acid oxidation, at least in part, by NAD+ dependent function of sirtuins. Therapeutically targeting sirtuins may provide a new class of inflammation and immune regulators. This review discusses how sirtuins integrate metabolism, bioenergetics, and immunity during inflammation and how sirtuin-directed treatment improves outcome in chronic inflammatory diseases and in the extreme stress response of sepsis.

Figure 1

Sirtuins and chronic inflammation: during homeostasis (grey arrow), there are small perturbations in sirtuin levels without inflammation. During chronic inflammatory states (denoted by pink), persistent decreases in SIRT1 levels/activity sustain glycolysis-dependent proinflammatory pathways. This immunometabolic inflexibility alters the bioenergy homeostasis set point, which is rebalanced by increasing SIRT1 activity.

Figure 2

Sirtuins and acute inflammation of sepsis: the extreme stress response of sepsis rapidly induces a systemic and potentially lethal hyperinflammatory state (red), which shifts within hours to a counterreactive hypoinflammation/adaptation phase (blue). NAD+ activation of sirtuins directs this switch. Mechanistically, nuclear SIRT1 levels briefly drop when homeostasis deviation initiates the glycolysis-dependent hyperinflammation, but within hours nuclear and mitochondrial sirtuin activation shifts glycolysis to fatty acid oxidation. This metabolic reprogramming globally represses immunity, affecting neutrophils, monocytes, dendritic cells, NK cells, and T lymphocytes. Resolution of acute inflammation and sepsis rebalances sirtuins and inflammation to restore homeostasis. Persistent elevation of sirtuins and hypoinflammation as a result lead to death (denoted by light blue area).

Figure 3

Sirtuins and obesity with sepsis: obesity is associated with low-sirtuin levels/activity, but mechanisms responsible for this imbalance are unknown. If sepsis occurs in obese individuals with low SIRT1, the early hyperinflammatory phase is accentuated and counteractive adaptation stage may be prolonged. Activating SIRT1 before obesity-associated sepsis prevents the accentuated acute inflammatory reaction.