SIRT在代谢调节中的作用.doc

Sirtuins as regulators of age-related disease and metabolismIntroductionSince the discovery of the yeast sirtuin silence information regulator 2 (Sir2) being able to extends yeast lifespan, Sirtuins have received significant attention and was originally described as a regulator of transcriptional silengcing of mating-type loci, telomeres and ribosomal DNA1,2. In mammals, the sirtuin family which involves 7 proteins (SIRT1-SIRT7) can be divided into 4 classes, and vary in tissue specificity, subcellular localization, enzymatic activity and targets (TABLE 1). Studies have proved the key roles of sirtuins in caloric restriction, age-related disease and metabolic homeostasis. Some other researches also discovered that the activation of sirtuins can relief disease relating to metabolism or neurodenegeration, such as type 2 diabetes and Parkinsons disease. As a consequence, regulation of sirtuins can be a potential method for age-related disease or metabolic disorder.In this article, I present my current knowledge about the regulation of sirtuins, namely SIRT1, SIRT5 and SIRT7 in age-related disease and metabolic homeostasis.NAD+ as a rate-limiting substrate for sirtuin deacylasesThe deacetylase activity of the sirtuin proteins requires NAD+ as a substrate, the density of which is determined by the nutritional state of the cell3. Therefor, NAD+ has a powerful metabolic impact by modulating the activity of sirtuins and their downstream effectors. It is well known that nicotinamide mononucleotide (NM) and nicotinamide riboside (NR) are NAD+ precursors, and DNA repair proteins, poly(ADP-ribose) polymerase proteins (PARP) - with PARP1 and PARP2 representing the main PARP activities in mammals are NAD+-consuming proteins4. Both activation of NM/NR and inactivation of PARP increased tissue NAD+ levels and activated mitochondrial metabolism5-7.In the research of Laurent Mouchiroud, et al.8, they show that NAD+ is causally reduced in aging, and PARP inhibitors or NAD+ precursors are able to increase mitochondrial function, thus prevent age-associated metabolic decline and promote longevity in worms. These effects are dependent upon the sirtuins deacetylazition, which involve the induction of mitonuclear protein imbalance, activation of stress signaling via the mitochondrial unfolded protein response (UPRmt)- a mitochondrial proteostasis pathway promoting longevity9, and the nuclear translocation and activation of FOXO transcription factor DAF-16- triggering an antioxidant protection program10. All these suggest that the modulation of NAD+ levels may be a potential method to improve mitochondrial function and prevent or treat age-related metabolic decline or diseases. TABLE 1 Sirtuin localization and function SirtuinClassLocalizationActivityTargetsSIRT1Nuleus,DeacetylationPGC1, FOXO1,cytosolFOXO3, p53,Notch, NF-B,HIF1, LXR, FXR,SREBP1c and moreSIRT2cytosolDeacetylationTubulin, PEPCK,FOXO1, PAR3SIRT3Mitochondria DeacetylationLCAD, HMGCS2,GDH, OXPHOScomplexes, SOD2,IDH2 and moreSIRT4Mitochondria ADP-ribosylationGDHSIRT5Mitochondria Deacetylation,CPS1demalonylation,desuccinylationSIRT6NuleusDeacetylation,H3K9,H5K56ADP-ribosylationSIRT7NucleolusUnknowUnknowSIRT1 in lipid/cholesterol regulationLipids and sterols play important roles in diverse biological processes in eukaryotes, such as membrane biosynthesis, intra-/extra-cellular signaling and energy storage. In humans, the imbalance of lipid and cholesterol may contribute to plenty of diseases relating to metabolic syndrome, such as obesity, insulin resistance, liver steatosis, hypertension, type 2 diabetes and cancer11. The alternation from lipid/cholesterol synthesis and fat storage to mobilization of fat during fasting may improve conditions with the metabolic disorder12,13. A improved understanding of fasting-dependent regulation of lipid/cholesterol metabolism can facilitate new therapeutic strategies to treat metabolic syndrome.The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes14.The mature nuclear forms of SREBP-1 and SREBP-2 are abundant in the mouse liver during feeding, and the expression of fatty acid and cholesterol biosynthesis genes is high, whereas, during fasting, SREBPs are markedly down-regulated, correlating with decreased lipogenic and cholesterogenic gene expression15.In the research of Amy K. Walker et al16, they confirm the conserved role of orthologs of SIRT1 in down-regulation of SREBP orthologs in fasting-dependent inhibition of lipid/cholesterol synthesis and fat storage. SIRT1 can directly deacetylate SREBP, resulting in SREBP ubiquitination, protein stability, and target gene expression. In addition, activators of SIRT1 such as SRT1720 inhibit SREBP gene expression in vivo and in vitro, correlating with decreased hepatic lipid/cholesterol level and attenuated liver steatosis in diet-induced or genetically obese mice. All these critical roles of SIRT1 suggests a novel way for the treatment of metabolic disorders relating to aberrant lipid/cholesterol homeostasis, such as metabolic syndrome.(for more detail information about the regulation of SIRT1 in lipid/cholesterol, see figure 1.)SIRT1 mediates central circadian controlIn mammals, systemic circadian regulation is accomplished through the central oscillator in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. The SCN responds to 24 hr light-dark (LD) cycles and coordinates rhythms of all aspects of circadian control, such as locomotor activity, hormone secretion, body temperature maintenance, feeding, so are other peripheral tissues, like liver. The aberrant circadian regulation results in plenty of pathologies, such as sleep disorders, diabetes and cancer17.In the research of Hung-Chun Chang and Leonard Guarente18, they show that the central circadian clock regulated by brain SIRT1 declining with age, and this regulation is governed by activating the transcription of the two major circadian regulators, BMAL1 and CLOCK. In aged wild-type mice and brain-specific SIRT1 knowout young mice, SIRT1 levels in SCN, BMAL1 and PER2 are all decreased, leading to a longer intrinsic period, a more disrupted activity pattern and an inability to adapt to changes in the light entrainment schedule. And these affects can be rescued by SIRT1-overexpression. All these suggest that SIRT1 plays a key role in age-related central control, and may be a cue for the treatment of circadian-related disease.SIRT5 regulates the urea cycleIn normal individuals, excess ammonia is produced when amino acids are used as energy sources, for example during fasting19.carbamoyl phosphate synthetase 1 (CPS1) is an enzyme catalyzing the initial step of the urea cycle for the detoxification and disposal of excess ammonia20, and patients with CPS1 deficiency suffer from hyperammonemia, which can lead to mental retardation and death21.In the research of Takashi Nakagawa et al22, they prove that SIRT5 is located in the mitochondrial matrix and directly deacetylates its substrate CPS1. They also show that SIRT5 is activated during fasting or high protein diet by the accumulation of NAD+, leading to increased deacetylation of CPS1 to adapt to the increasing amino acid catabolism. Conversely, SIRT5-knockout mice fail to activate CPS1 and show high blood ammonia during fasting or high-protein diet. All these denote the pivotal roles of SIRT5 in ammonia detoxification/disposal by activating CPS1.SIRT7 activates RNA polymerase I transcriptionSome studies have found an elevated SIRT7 expression in several human cancers23-25. However, O. Vakhrusheva, et al found a SIRT7-dependent inhibition of cell growth and proliferation and SIRT7 expression is reduced in several cancerogenic cell lines26. Olesya Vakhrusheva, et al find that SIRT7-deficient animals undergo a reduction in mean and maximum lifespans and develop heart hypertrophy and inflammatory cardiomyopathy27. But the molecular targets, potential enzymatic activity and the detail mechanism to affect lifespan or disease of SIRT7 have not been identified yet. RNA polymerase I is used in the process of rRNA synthesis. In the research of Ethan Ford, et al.28, they show that SIRT7 is widely expressed in nucleolus, and is associated with the activation of rRNA genes (rDNA), where it interacts with RNA polymerase I (pol I) and histones. Overexpression of SIRT7 increases Pol I-mediated transcription, whereas knockdown of SIRT7 or inhibition of the catalytic activity results in decreased association of Pol I with rDNA and a reduction of Pol I transcription. Depletion of SIRT7 stops cell proliferation and triggers apoptosis. All these suggest that SIRT7 is a positive regulator of Pol I transcription and is required for cell viability in mammals.Conclusion Since the discovery that Sir2 can extend lifespan of yeast, the sirtuins family was expected to act the same role in mammals. However, controversial results have been found about the regulation or function of the sirtuin family. For example, SIRT1 transgenic mice display reduced cancer risk and are protected from metabolic dysfunction associated with aging but do not show increased lifespan28. So a rising hypothesize was that SIRT1 activity may determine healthspan rather than natural lifespan. Future research have to be designed to determine the function of other sirtuin proteins.As we can see in table 1, the sirtuin family are scattered in different subcellular location, and they will regulate the cellar function in different levels, such as transcription, translation or post translation, et al. Besides, they have different up-/down-regulators and targets. Their sharing of some regulators and targets indicate that they may have interconnect effects and a insidious net may exist and need further studies. For example, p53 can be deacetylated by both SIRT1 and SIRT7, but how these two sirtuins interconnect on p53 and interact with each other have to be further researched.From the relevance of sirtuins regulation and age-related disease described aboved, it would be worthwhile to test more activators or inhibitors of sirtuins, and exploit these factors in the treatment of metabolism-related diseases or extending the healthspan.Figure 1. Overview of the role of sirtuins in the regulation of lipid metabolism. a. Transcriptional regulation of lipid homeostasis in the nucleus. SIRT1 inhibits lipid synthesis by deacetylating, and thereby destabilizing, sterol-response element-binding protein 1c (SREBP1c), a downstream target of liver X receptor (LXR), which is the key transcription factor involved in lipid synthesis. SIRT1 also inhibits lipid synthesis by suppressing the activity of peroxisome proliferator-activated receptor- (PPAR). SIRT1 promotes fatty acid oxidation by activating PPAR and PPAR co-activator 1 (PGC1) and promoting the expression of their target genes. Blank ovals represent multiple transcription factors. b. Overview of the lipid cycle showing where sirtuins act. Once taken up by the cell by fatty acid transporters, fatty acids are transported to mitochondria, where they are oxidized to produce ATP. Fat breakdown can also lead to the generation of ketone bodies through the action of 3_hydroxy-3_methylglutaryl CoA synthase 2 (HMGCS2). Fatty acids can be synthesized (lipogenesis, dashed arrows) in the cytosol from malonyl CoA by fatty acid synthase and then converted to triglycerides. During periods of high energy demand, triglycerides can be broken down to free fatty acids (lipolysis, occurring mainly in fat tissue), which are then released into the circulation. SIRT1 reduces fatty acid storage by enhancing lipolysis through the inhibition of PPAR and by decreasing fatty acid synthesis through SREBP1c. In addition, SIRT6 may act as a repressor of genes involved in fatty acid synthesis. SIRT3 stimulates _oxidation and ketone body formation by targeting and activating long-chain acyl CoA dehydrogenase (LCAD) and HMGCS2, respectively. Furthermore, SIRT3 decreases reactive oxygen species (ROS) production by stimulating superoxide dismutase 2 (SOD2), and SIRT3 also enhances cellular respiration by increasing the activities of complex I, complex II, complex III and isocitrate dehydrogenase 2 (IDH2). SIRT4 seems to dampen the transcription of genes governing fatty acid oxidation. NCoR1, nuclear receptor co-repressor 1; Pi, inorganic phosphate; SDH, succinate dehydrogenase; SMRT, silencing mediator of retinoid and thyroid hormone receptors. REFERENCES1. Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. 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