Protein deacetylation by SIRT1: an emerging key post-translational modification in metabolic regulation

Abstract

The biological function of most proteins relies on reversible post-translational modifications, among which phosphorylation is most prominently studied and well recognized. Recently, a growing amount of evidence indicates that acetylation-deacetylation reactions, when applied to crucial mediators, can also robustly affect the function of target proteins and thereby have wide-ranging physiological impacts. Sirtuin 1 (SIRT1), which functions as a nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylase, deacetylates a wide variety of metabolic molecules in response to the cellular energy and redox status and as such causes significant changes in metabolic homeostasis. This review surveys the evidence for the emerging role of SIRT1-mediated deacetylation in the control of metabolic homeostasis.

Fig. 1

The role of protein deacetylation by SIRT1 in the control of metabolic homeostasis in response to nutrient and environmental stimuli. The deacetylase activity of SIRT1 is shaped and fine-tuned through its protein level, post-translational modifications, and association with inhibitors or cofactors. Most importantly, SIRT1 activity depends on the availability of cellular NAD⁺, which is orchestrated by the cellular redox status, NAD⁺ synthesis, and utilization in response to the nutrient and environment. The activated SIRT1 modulates many aspects of glucose and lipid homeostasis through deacetylating key metabolic molecules. The deacetylation of PGC1α by SIRT1 activates its transcriptional activity and thus induces the expression of target genes involved in gluconeogenesis and fatty acid oxidation. The SIRT1-mediated deacetylation of FOXO1 also increases its transcriptional activity and promotes the expression of gluconeogenic genes in liver, insulin gene in pancreas, and adiponectin gene in the adipose tissues. The sterol sensors LXRs are deacetylated and activated by SIRT1. The deacetylation contributes to balance cholesterol homeostasis in vivo. In addition, SIRT1 is capable to deacetylate and activate the cytoplasmic AceCS1, which scavenges acetate to usable acetyl-CoA. SIRT1 boosts and maintains gluconeogenesis in response to low nutrients by deacetylating and inhibiting other two transcription (co)factors CRTC2 and STAT3. The deacetylation of CRTC2 promotes its degradation whereas the STAT3 deacetylation renders STAT3 in the cytoplasm and prevents its inhibition on PGC1α expression. Similarly, the deacetylation of NF-κB by SIRT1 abrogates the nuclear translocation of NF-κB. This results in a decreased expression of iNOS gene in pancreas and preserves the viability and insulin secretion function of islets. In adipose tissues, the inhibition of NF-κB function via SIRT1 deacetylation decreases the inflammatory gene expression and correspondingly improves the insulin sensitivity.

Fig. 2

A two-step induction of NAD⁺ levels by AMPK activation. AMPK, activated by the nutrient deprivation or energy stress, enhances NAD⁺ levels through two steps. The initial acute metabolic phase relies on the boost in fatty acid oxidation. The second slow transcription phase depends on the induction of Nampt expression. Altogether, a higher level of NAD⁺ is obtained, which activates SIRT1.

Fig. 3

A circadian feedback loop between SIRT1 activity and Nampt transcription. The core circadian regulators Clock/Bmal1 bind to the E-box of Nampt gene. Clock acetylates Bmal1 and local histone tails to promote the transcription of Nampt. The resulting Nampt enzyme boosts the synthesis of NAD⁺, which activates SIRT1. Meanwhile, other two Clock/Bmal1 targets Cry1 and Per2 are induced by Clock/Bmal1. The Cry1/Per2 heterodimer, serving as corepressors of Clock/Bmal1, turns off the transcription of Clock/Bmal1 target genes, including Nampt. The activated SIRT1 is subsequently recruited to the transcriptional machinery by Clock and deacetylates Bmal1 and Per2. This deacetylation promotes the degradation of both proteins. As such, the promoter region of Nampt is re-primed and the gene is ready for the next round of Clock-dependent induction.