Brain SIRT1 Mediates Metabolic Homeostasis and Neuroprotection

Abstract

Sirtuins are evolutionarily conserved proteins that use nicotinamide adenine dinucleotide (NAD⁺) as a co-substrate in their enzymatic reactions. There are seven proteins (SIRT1-7) in the human sirtuin family, among which SIRT1 is the most conserved and characterized. SIRT1 in the brain, in particular, within the hypothalamus, plays crucial roles in regulating systemic energy homeostasis and circadian rhythm. Apart from this, SIRT1 has also been found to mediate beneficial effects in neurological diseases. In this review, we will first summarize how SIRT1 in the brain relates to obesity, type 2 diabetes, and circadian synchronization, and then we discuss the neuroprotective roles of brain SIRT1 in the context of cerebral ischemia and neurodegenerative disorders.

Keywords: Alzheimer's disease; Parkinson's disease; Sirt1; cerebral ischemia; circadian rhythms; obesity; type 2 diabetes mellitus.

Figure 1

An overview of brain SIRT1 in metabolic and neurological disorders. Brain SIRT1 activity is dependent on NAD⁺ levels, which increases under energy crisis, and decline with high energy load. Any dysregulation of brain SIRT1 activity can have devastating consequences in terms of mitochondrial function, metabolic homeostasis, circadian synchronization, and neurological function. A proper function of brain SIRT1 is protective against obesity, diabetes, circadian dysregulation. In addition, brain SIRT1 exerts neuroprotection against ischemic injury and neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). T2DM, type 2 diabetes, NAD⁺, nicotinamide adenine dinucleotide.

Figure 2

A simplified overview of mitochondrial functions mediated by SIRT1 activity. SIRT1 may interact with transcription factors or mitochondrial proteins to induce different effects related to mitochondrial function—a select few of these proteins are highlighted. SIRT1 can suppress Uncoupling protein 2 (UCP-2) in the inner mitochondrial membrane to increase levels of ATP, which is important for energy metabolism. SIRT1 may also deacetylate Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) to induce its activation and augment mitochondrial biogenesis by increasing mitochondrial gene expression via Nuclear respiratory factor 1 (NRF-1) and Nuclear-encoded mitochondrial transcription factor A (TFAM). PGC-1α itself can regulate different metabolic processes and may potentially play a role in mitophagy.

Figure 3

Regulative mechanisms of brain SIRT1 in metabolic homeostasis. Brain SIRT1 increases energy expenditure via the hypothalamic pituitary thyroid axis and increased sympathetic nerve activity in the adipose tissue. In addition, hormones, such as leptin, insulin, and ghrelin through brain SIRT1 to balance energy expenditure and energy intake. For example, SIRT1 in POMC neurons deacetylate Forkhead box protein O1 (FOXO1) to increase the insulin signal pathway.

Figure 4

The regulation of central and peripheral clock genes by SIRT1. When dimerized, the core clock genes CLOCK and BMAL1 promote the expression of several downstream genes including their own negative regulators periods (PER) and cryptochromes (CRY). PER and CRY accumulate during the day and together with casein kinase 1 (CK1) then repress their own transcription. The CLOCK-BMAL1 complex also regulates the retinoic acid-related orphan receptors (ROR) and the nuclear receptors (Rev-Erb), which compete for the regulation of the BMAL1 promoter. In the peripheral clocks, SIRT1 regulates the circadian genes at different levels. SIRT1 protein levels cycle in a circadian manner, and through its rhythmic binding to the CLOCK-BMAL1 complex SIRT1 promotes the circadian transcription of Bmal1, Rorγ, Per2, and Cry1. SIRT1 also promotes the deacetylation and degradation of the PER2 protein. SIRT1 activity has also been reported to cycle in a circadian manner owing to the rhythmic expression of NAMPT, a crucial enzyme for NAD⁺ biosynthesis, by the CLOCK-BMAL1 complex. In turn, SIRT1 also acts as a negative regulator of the CLOCK-BMAL1 complex thus preventing the activation of circadian promoters. In the suprachiasmatic nucleus (SCN), SIRT1 activates the transcription of the circadian genes BMAL1 and CLOCK through PGC-1α.

Figure 5

SIRT1 levels in the suprachiasmatic nucleus (SCN) are disrupted by aging and Alzheimer's disease. The rhythmic expression of SIRT1 in the SCN has been reported to be disrupted in animal models of aging and Alzheimer's disease. This, in turn, disrupts the circadian expression of clock genes causing a disruption in the activity patterns of mice and their entrainment to light. The overexpression of SIRT1 protected mice from these age-dependent effects. Similarly, the administration of fat, ketone bodies, or nicotinamide rescued the circadian expression of clock genes in Alzheimer's disease mouse models and restored their locomotor rhythmicity.

Figure 6

SIRT1 protects against cerebral ischemic injury in multiple mechanisms. SIRT1 deacetylate p53 to block the p53-induced apoptotic pathway, thus, promoting neuronal survival. SIRT1 deacetylates endothelial nitric oxide synthase (eNOS) to regulate vascular tone and maintain brain blood flow. SIRT1protects against white matter injury in ischemic injury, possible via promoting the oligodendrocyte regeneration. Finally, SIRT1 is required for ischemic preconditioning (IPC) and resveratrol preconditioning (RPC) induced ischemic neuroprotection. Arg, L-arginine, NO, nitric oxide.

Figure 7

Therapeutic mechanisms of SIRT1 in neurodegenerative disease. The left panel represents SIRT1 in Parkinson's disease (PD). SIRT1 deacetylates microtubule-associated protein 1A/1B-light chain 3 (LC3) in the nucleus which induces the translocation of LC3 into the cytoplasm. In the cytoplasm, SIRT1 and AMP-activated Protein Kinase (AMPK) coordinate to activate LC3-phosphatidylethanolamine (LC3-II). These mechanisms lead to increased autophagic clearance of α-synuclein, reducing α-synuclein deposits. In the middle panel, SIRT1's role in Alzheimer's disease (AD) is represented. SIRT1 can directly deacetylate acetylated-tau protein, increasing its susceptibility to degradation and prevent tau from forming neurofibrillary tangles. SIRT1 can also deacetylate peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α), which increases its transcriptional regulation activity. After being deacetylated, PGC-1α can instill transcriptional repression of β-secretase, which in turn can reduce the level of amyloid-β production and neuritic senile plaque accumulation. The right panel represents Huntington's disease (HD). SIRT1 deacetylates CREB-regulated transcription coactivator 1 (TORC1), which allows TORC1 to activate cAMP response element-binding protein (CREB). CREB then transcriptionally upregulates brain-derived neurotrophic factor (BDNF). The increase in BDNF promotes neurotrophic and neuroprotective mechanisms against HD pathology.