Dependent Protein Deacetylase SIRT1 Research Articles

Nicotinamide mononucleotide induces lipolysis by regulating ATGL expression via the SIRT1-AMPK axis in adipocytes

Nicotinamide adenine dinucleotide (NAD+) -dependent protein deacetylase SIRT1 plays an important role in the regulation of metabolism. Although the administration of nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to ameliorate metabolic disorders, such as insulin resistance and glucose intolerance, the direct effect of NMN on the regulation of lipid metabolism in adipocytes remains unclear. We here investigated the effect of NMN on lipid storage in 3T3-L1 differentiated adipocytes. Oil-red O staining showed that NMN treatment reduced lipid accumulation in these cells. NMN was found to enhance lipolysis in adipocytes since the concentration of glycerol in the media was increased by NMN treatment. Western blotting and real-time RT-PCR analysis revealed that adipose triglyceride lipase (ATGL) expression at both protein and mRNA level was increased with NMN treatment in 3T3-L1 adipocytes. Whereas NMN increased SIRT1 expression and AMPK activation, an AMPK inhibitor compound C restored the NMN-dependent upregulation of ATGL expression in these cells, suggesting that NMN upregulates ATGL expression through the SIRT1-AMPK axis. NMN administration significantly decreased subcutaneous fat mass in mice on a high-fat diet. We also found that adipocyte size in subcutaneous fat was decreased with NMN treatment. Consistent with the alteration of fat mass and adipocyte size, the ATGL expression in subcutaneous fat was slightly, albeit significantly, increased with NMN treatment. These results indicate that NMN suppresses subcutaneous fat mass in diet-induced obese mice, potentially in part via the upregulation of ATGL. Unexpectedly, the reduction in fat mass as well as ATGL upregulation with NMN treatment were not observed in epididymal fat, implying that the effects of NMN are site-specific in adipose tissue. Thus, these findings provide important insights into the mechanism of NMN/NAD+ in the regulation of metabolism.

Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1.

The expansion of CD8+CD28- T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28- T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28- T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28- T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28- T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28- T cells. These data identify the evolutionarily conserved SIRT1-FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.

ID3008 Differential expression of circadian genes in leukemia and a possible role for Sirt1 in restoring the circadian clock in chronic myeloid leukemia


 Dis-regulation of genes making up the mammalian circadian clock has been associated with different forms of cancer. This study initially aimed to address how the circadian clock genes behave over the course of treatment for both the acute and chronic forms of leukemia and whether any could be used as potential biomarkers as a read-out for therapeutic efficacy. Expression profiling for both core and peripheral clock genes revealed that the majority of clock genes are down-regulated in AML patients apart from Cry2 which is up-regulated towards the end of treatment. A similar observation was seen in ALL patients however here, Cry2 expression came back up towards control levels upon treatment completion. In addition, all of the core clock genes are down-regulated in both chronic forms of leukemia (CML and CLL) apart from Cry2 which is not affected when the disease is diagnosed. Furthermore, the NAD(+) – dependent protein deacetylase Sirt1 has been proposed to have a dual role in both control of circadian clock circuitry as well as promotion of cell survival by inhibiting apoptotic pathways in cancer. We used a pharmacological-based approach to see whether Sirt1 played a role in regulating the circadian clock circuitry in both Acute and Chronic forms of leukemia. Our results suggest that interfering with Sirt1 leads to a partial restoration of BMAL1 oscillation in CML patient samples. Furthermore, interfering with Sirt1 activity leads to both the induction and repression of circadian clock genes in both Acute and chronic forms of leukemia and therefore makes it a potential therapeutic target to either augment existing therapies for chronic leukemia or to act as a means of facilitating chronotherapy in order to maximize both the effectiveness of existing therapies and to minimize therapy-associated toxicity.

Computational model of circadian oscillator in mammals: Interaction with NAD+/SIRT1 system and age-related changes in the expression of circadian oscillator genes

The studies of the last decade allow us to look in a new way at the possible association between the aging processes and the circadian rhythm. One of the promising directions in this area appeared thanks to the new data on the involvement of the NAD+-dependent protein deacetylase SIRT1 in the integration of the pathways of the circadian rhythm and metabolism regulation and the new NAD+ function as a “metabolic oscillator”. We present the a modification and extension of the most detailed circadian oscillator (CO) model developed in 2012 by J.K. Kim and D.B. Forger. The additional oscillator feedback with the involvement of NAMPT, SIRT1 genes/proteins, as well as NAM and NAD+, is included in it. The involvement of the CLOCK/BMAL1 transcription factor in regulating the NAMPT gene transcription determines the appropriate rhythm of mRNA expression and the NAMPT protein. Since the enzyme (this gene product) is a key in the pathway of NAD+ biosynthesis and recycling, the circadian rhythm is also typical for the fluctuation of this coenzyme level and the activity of NAD+-dependent protein deacetylase SIRT1. The deacetylation of the CO components by this enzyme closes the feedback mediated by this pathway. In particular, an increase in the Per2 protein degradation, an increase in the Bmal1 gene transcription, and the deacetylation of the chromatin of the regulatory regions of the CO genes in the area of E-boxes with subsequent transcription suppression can be revealed among the SIRT1 effects in the CO. All these processes are presented in the extended CO model that we suggested. Based on the experimental data about changes in the SIRT1 activity and NAD+ level with age, an attempt to study the effect of these age-related changes on the functioning of a CO was made. The modeling data indicate a decrease in the expression level of a number of CO genes (particularly the Bmal1 and Per2) in older age groups. An increase in the period of circadian oscillations was also registered. The results obtained indicate that a decrease in the SIRT1 activity associated with the age-related violation of the NAD+ metabolism can be one of the reasons for the violations of the functioning of a CO in the suprachiasmatic nuclei (SCN). Such violations can also entail violations of the organism’s circadian rhythms in general.

Temporal overexpression of SIRT1 in skeletal muscle of adult mice does not improve insulin sensitivity or markers of mitochondrial biogenesis.

Activation of the NAD+ dependent protein deacetylase SIRT1 has been proposed as a therapeutic strategy to treat mitochondrial dysfunction and insulin resistance in skeletal muscle. However, lifelong overexpression of SIRT1 in skeletal muscle does not improve parameters of mitochondrial function and insulin sensitivity. In this study, we investigated whether temporal overexpression of SIRT1 in muscle of adult mice would affect skeletal muscle mitochondrial function and insulin sensitivity. To circumvent potential effects of germline SIRT1 overexpression, we utilized an inducible model of SIRT1 overexpression in skeletal muscle of adult mice (i-mOX). Insulin sensitivity was assessed by 2-deoxyglucose uptake, muscle maximal respiratory function by high-resolution respirometry and systemic energy expenditure was assessed by whole body calorimetry. Although SIRT1 was highly, and specifically, overexpressed in skeletal muscle of i-mOX compared to WT mice, glucose tolerance and skeletal muscle insulin sensitivity were comparable between genotypes. Additionally, markers of mitochondrial biogenesis, muscle maximal respiratory function and whole-body oxygen consumption were also unaffected by SIRT1 overexpression. These results support previous work demonstrating that induction of SIRT1 in skeletal muscle, either at birth or in adulthood, does not impact muscle insulin action or mitochondrial function.

A novel SIRT1 inhibitor, 4bb induces apoptosis in HCT116 human colon carcinoma cells partially by activating p53

The NAD+-dependent protein deacetylase SIRT1 has emerged as an important target for epigenetic therapeutics of colon cancer as its increased expression is associated with cancer progression. Additionally, SIRT1 represses p53 function via deacetylation, promoting tumor growth. Therefore, inhibition of SIRT1 is of great therapeutic interest for the treatment of colon cancer. Here, we report discovery of a novel quinoxaline based small molecule inhibitor of human SIRT1, 4bb, investigated its effect on viability of colon cancer cells and molecular mechanism of action. In vitro, 4bb is a significantly more potent SIRT1 inhibitor, compared to β-naphthols such as sirtinol, cambinol. Increasing concentration of 4bb decrease viability of colon cancer cells but, does not affect the viability of normal dermal fibroblasts depicting cancer cell specificity. Further, 4bb treatment increased p53 acetylation, Bax expression and induced caspase 3 cleavage suggesting that the death of HCT116 colon cancer cells occur through intrinsic pathway of apoptosis. Overall, our results presents 4bb as a new class of human SIRT1 inhibitor and suggest that inhibition of SIRT1 by 4bb induces apoptosis of colon cancer cells at least in part via activating p53 by preventing p53 deacetylation, increasing Bax expression and inducing caspases. Therefore, this molecule provide an opportunity for lead optimization and may help in development of novel, non-toxic epigenetic therapeutics for colon cancer.

Differential Expression of Circadian Genes in Leukemia and a Possible Role for Sirt1 in Restoring the Circadian Clock in Chronic Myeloid Leukemia.

Disregulation of genes making up the mammalian circadian clock has been associated with different forms of cancer. This study aimed to address how the circadian clock genes behave over the course of treatment for both the acute and chronic forms of leukemia and whether any could be used as potential biomarkers as a read-out for therapeutic efficacy. Expression profiling for both core and ancillary clock genes revealed that the majority of clock genes are down-regulated in acute myeloid leukemia patients, except for Cry2, which is up-regulated towards the end of treatment. A similar process was seen in acute lymphocytic leukemia patients; however, here, Cry2 expression came back up towards control levels upon treatment completion. In addition, all of the core clock genes were down-regulated in both chronic forms of leukemia (chronic myeloid leukemia and chronic lymphocytic leukemia), except for Cry2, which was not affected when the disease was diagnosed. Furthermore, the NAD(+) – dependent protein deacetylase Sirt1 has been proposed to have a dual role in both control of circadian clock circuitry and promotion of cell survival by inhibiting apoptotic pathways in cancer. We used a pharmacological-based approach to see whether Sirt1 played a role in regulating the circadian clock circuitry in both acute and chronic forms of leukemia. Our results suggest that interfering with Sirt1 leads to a partial restoration of BMAL1 oscillation in chronic myeloid leukemia patient samples. Furthermore, interfering with Sirt1 activity led to both the induction and repression of circadian clock genes in both acute and chronic forms of leukemia, which makes it a potential therapeutic target to either augment existing therapies for chronic leukemia or to act as a means of facilitating chronotherapy in order to maximize both the effectiveness of existing therapies and to minimize therapy-associated toxicity.

Adipose tissue NAD+ biology in obesity and insulin resistance: From mechanism to therapy.

Nicotinamide adenine dinucleotide (NAD+ ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD+ biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD+ biosynthesis, together with its key downstream mediator, namely the NAD+ -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD+ biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD+ biology.

The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD+/SIRT1 in mammalian aging and longevity control.

The original concept of the NAD World was proposed in 2009, providing a comprehensive framework to investigate critical issues of biological robustness and trade-offs in mammalian aging and longevity control. Significant progress has been made over the past 7 years, advancing our understanding of the mechanisms by which biological robustness is maintained, and providing extensive support to the concept of the NAD World. Three key organs and tissues have been identified as basic elements in this control system for mammalian aging and longevity: the hypothalamus as the control center of aging, skeletal muscle as an effector, and adipose tissue as a modulator. While the hypothalamus sends a signal to skeletal muscle through the sympathetic nervous system, adipose tissue remotely regulates hypothalamic function by coordinating NAD+ biosynthesis at a systemic level. Skeletal muscle might also communicate with other organs and tissues by secreting various myokines. The mammalian NAD+-dependent protein deacetylase SIRT1 and the key NAD+ biosynthetic enzyme NAMPT mediate these inter-tissue communications. In this review, the function of each organ or tissue and their inter-tissue communications will be discussed in terms of understanding mammalian aging and longevity control. With such an emphasis on the system architecture, the concept is now reformulated as the NAD World 2.0, providing several important predictions. The concept of the NAD World 2.0 will provide a new foundation to understand a control system for mammalian aging and longevity and accelerate the development of an effective anti-aging intervention for humans.

The N-Terminal Domain of SIRT1 Is a Positive Regulator of Endogenous SIRT1-Dependent Deacetylation and Transcriptional Outputs.

The NAD+-dependent protein deacetylase SIRT1 regulates energy metabolism, responses to stress, and aging by deacetylating many different proteins, including histones and transcription factors. The mechanisms controlling SIRT1 enzymatic activity are complex and incompletely characterized, yet essential for understanding how to develop therapeutics that target SIRT1. Here, we demonstrate that the N-terminal domain of SIRT1 (NTERM) can trans-activate deacetylation activity by physically interacting with endogenous SIRT1 and promoting its association with the deacetylation substrate NF-κB p65. Two motifs within the NTERM domain contribute to activation of SIRT1-dependent activities, and expression of one of these motifs in mice is sufficient to lower fasting glucose levels and improve glucose tolerance in a manner similar to overexpression of SIRT1. Our results provide insights into the regulation of SIRT1 activity and a rationale for pharmacological control of SIRT1-dependent activities.

Epigenetics and the Control of the Collecting Duct Epithelial Sodium Channel

The apical membrane epithelial Na(+) channel subunit (ENaC) in series with the basolateral Na(+)/K(+)-adenosine triphosphatase mediates collecting duct Na(+) reabsorption. Aldosterone induces αENaC gene transcription, which appears to be rate limiting for ENaC activity in this segment. Although this response has long been assumed to be solely the result of liganded nuclear hormone receptors trans-activating αENaC, epigenetic controls of basal and aldosterone-induced transcription of αENaC in the collecting duct recently were described. These epigenetic pathways involve dynamic nuclear repressor complexes targeted to specific subregions of the αENaC promoter and consisting of the histone methyltransferase disrupter of telomeric silencing (Dot)1a together with the transcriptional factor Af9 or the nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase Sirt1, key co-regulatory proteins, including serum- and glucocorticoid-induced kinase-1 and the putative transcription factor Af17, and targeted chromatin modifications. The complexes, through the action of Dot1a, maintain chromatin associated with the αENaC promoter in a stable hypermethylated state, constraining αENaC transcription under basal conditions. Aldosterone and serum- and glucocorticoid-induced kinase-1, itself, activate αENaC transcription in large part by disrupting or diminishing the Dot1a-Af9 and Dot1a-Sirt1 complexes and their effects on chromatin. Mouse models indicate potential roles of the Dot1a pathways in renal salt excretion and hypertension.

Fasting Protects the Brain

Neuroscience Fasting has been shown to slow aging in a number of species. Caloric restriction acts on many different cell types and tissues and, importantly, also on the brain. There, it leads to a slowing-down of age-associated pathologies, such as brain atrophy or loss of synaptic plasticity. Moreover, in several animal models, a reduced consumption of calories seems to protect against cognitive deficits such as memory loss. However, it is not known whether caloric restriction can delay the beginning of neurodegeneration. The mechanisms underlying these observations are also largely unclear. In experiments using genetically modified mice, Graff et al. found that caloric restriction effectively delayed the onset of neurodegeneration and preserved structural and functional synaptic plasticity as well as memory capacities. Fasting activated the expression and activity of the nicotinamide adenine dinucleotide (NAD)–dependent protein deacetylase SIRT1, a known promoter of neuronal life span. Surprisingly, this effect of reduced consumption of calories could be mimicked by a small-molecule SIRT1-activating compound. Mice treated with this substance recapitulated the beneficial effects of caloric restriction against neurodegeneration-associated pathologies. If this mechanism also applies to humans, SIRT1 may represent an appealing pharmacological target against neurodegeneration. J. Neurosci. 33 , 8951 (2013).

Rejuvenating SIRT1 Activators

Whether the red wine component resveratrol directly activates the NAD(+)-dependent protein deacetylase SIRT1 has been debated. A recent study by Hubbard etal. (2013) strengthens the case that SIRT1-activating compounds (STACs) function as positive allosteric regulators of SIRT1 and thereby regulate mitochondrial function.

Resveratrol Improves Cardiomyopathy in Dystrophin-deficient Mice through SIRT1 Protein-mediated Modulation of p300 Protein*[S

Cardiomyopathy is the main cause of death in Duchenne muscular dystrophy. Here, we show that oral administration of resveratrol, which leads to activation of an NAD(+)-dependent protein deacetylase SIRT1, suppresses cardiac hypertrophy and fibrosis and restores cardiac diastolic function in dystrophin-deficient mdx mice. The pro-hypertrophic co-activator p300 protein but not p300 mRNA was up-regulated in the mdx heart, and resveratrol administration down-regulated the p300 protein level. In cultured cardiomyocytes, cardiomyocyte hypertrophy induced by the α(1)-agonist phenylephrine was inhibited by the overexpression of SIRT1 as well as resveratrol, both of which down-regulated p300 protein levels but not p300 mRNA levels. In addition, activation of atrial natriuretic peptide promoter by p300 was inhibited by SIRT1. We found that SIRT1 induced p300 down-regulation via the ubiquitin-proteasome pathway by deacetylation of lysine residues for ubiquitination. These findings indicate the pathological significance of p300 up-regulation in the dystrophic heart and indicate that SIRT1 activation has therapeutic potential for dystrophic cardiomyopathy.

Resveratrol Rescues SIRT1-Dependent Adult Stem Cell Decline and Alleviates Progeroid Features in Laminopathy-Based Progeria

Abnormal splicing of LMNA gene or aberrant processing of prelamin A results in progeroid syndrome. Here we show that lamin A interacts with and activates SIRT1. SIRT1 exhibits reduced association with nuclear matrix (NM) and decreased deacetylase activity in the presence of progerin or prelamin A,leading to rapid depletion of adult stem cells (ASCs) in Zmpste24(-/-) mice. Resveratrol enhances the binding between SIRT1 and A-type lamins to increases its deacetylase activity. Resveratrol treatment rescues ASC decline, slows down body weight loss, improves trabecular bone structure and mineral density, and significantly extends the life span in Zmpste24(-/-) mice. Our data demonstrate lamin A as an activator of SIRT1 and provide a mechanistic explanation for the activation of SIRT1 by resveratrol. The link between conserved SIRT1 longevity pathway and progeria suggests a stem cell-based and SIRT1 pathway-dependent therapeutic strategy for progeria.

Resveratrol Supplementation Does Not Improve Metabolic Function in Nonobese Women with Normal Glucose Tolerance

Resveratrol has been reported to improve metabolic function in metabolically abnormal rodents and humans, but it has not been studied in nonobese people with normal glucose tolerance. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the metabolic effects of 12weeks of resveratrol supplementation (75mg/day) in nonobese, postmenopausal women with normal glucosetolerance. Although resveratrol supplementation increased plasma resveratrol concentration, it did not change body composition, resting metabolic rate, plasma lipids, or inflammatory markers. A two-stage hyperinsulinemic-euglycemic clamp procedure, in conjunction with stable isotopically labeled tracer infusions, demonstrated that resveratrol did not increase liver, skeletal muscle, or adipose tissue insulin sensitivity. Consistent with the absence of invivo metabolic effects, resveratrol did not affect its putative molecular targets, including AMPK, SIRT1, NAMPT, and PPARGC1A, in either skeletal muscle or adipose tissue. These findings demonstrate that resveratrol supplementation does not have beneficial metabolic effects innonobese, postmenopausal women with normal glucose tolerance.

Differential Cell-Protective Function of Two Resveratrol (Trans-3,5,4′-trihydroxystilbene) Glucosides against Oxidative Stress

Resveratrol (trans-3,5,4'-trihydroxystilbene; RSV), a natural polyphenol, exerts a beneficial effect on health and diseases. RSV targets and activates the NAD(+)-dependent protein deacetylase SIRT1; in turn, SIRT1 induces an intracellular antioxidative mechanism by inducing mitochondrial superoxide dismutase (SOD2). Most RSV found in plants is glycosylated, and the effect of these glycosylated forms on SIRT1 has not been studied. In this study, we compared the effects of RSV and two glycosyl RSVs, resveratrol-3-O-β-d-glucoside (3G-RSV; polydatin/piceid) and resveratrol-4'-O-β-d-glucoside (4'G-RSV), at the cellular level. In oxygen radical absorbance capacity and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays, the antioxidant activity of 3G-RSV was comparable to that of RSV, whereas the radical-scavenging efficiency of 4'G-RSV was less than 50% of that of RSV. However, 4'G-RSV, but not 3G-RSV, induced SIRT1-dependent histone H3 deacetylation and SOD2 expression in mouse C2C12 skeletal myoblasts; as with RSV, SIRT1 knockdown blunted these effects. RSV and 4'G-RSV, but not 3G-RSV, mitigated oxidative stress-induced cell death in C2C12 cells and primary neonatal rat cardiomyocytes. RSV and 4'G-RSV inhibited C2C12 cell proliferation, but 3G-RSV did not. RSV was found in both the intracellular and extracellular fractions of C2C12 cells that had been incubated with 4'G-RSV, indicating that 4'G-RSV was extracellularly deglycosylated to RSV, which was then taken up by the cells. C2C12 cells did not deglycosylate 3G-RSV. Our results point to 4'G-RSV as a useful RSV prodrug with high water solubility. These data also show that the in vitro antioxidative activity of these molecules did not correlate with their ability to protect cells from oxidative stress-induced apoptosis.

Cardioprotective mIGF-1/SIRT1 signaling induces hypertension, leukocytosis and fear response in mice

Locally acting insulin growth factor isoform (mIGF-1) and the NAD+-dependent protein deacetylase SIRT1 are implicated in life and health span. Heart failure is associated with aging and is a major cause of death. mIGF-1 protects the heart from oxidative stresses via SIRT1. SIRT1 subcellular localization and its genomic regulation by mIGF-1 are unknown. We show here that SIRT1 is located in the nuclei of a significant fraction of cardiomyocytes. Using high throughput sequencing approaches in mIGF-1 transgenic mice, we identified new targets of the mIGF-1/SIRT1 signaling. In addition to its potent cardioprotective properties, cardiac-restricted mIGF-1 transgene induced systemic changes such as high blood pressure, leukocytosis and an enhanced fear response, in a SIRT1-dependent manner. Cardiac mIGF-1/ SIRT1 signaling may thus modulate disparate systemic functions.

MIGF‐1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart

Oxidative stress contributes to the pathogenesis of aging-associated heart failure. Among various signaling pathways mediating oxidative stress, the NAD(+) -dependent protein deacetylase SirT1 has been implicated in the protection of heart muscle. Expression of a locally acting insulin-like growth factor-1 (IGF-1) propeptide (mIGF-1) helps the heart to recover from infarct and enhances SirT1 expression in cardiomyocytes (CM) in vitro, exerting protection from hypertrophic and oxidative stresses. To study the role of mIGF-1/SirT1 signaling in vivo, we generated cardiac-specific mIGF-1 transgenic mice in which SirT1 was depleted from adult CM in a tamoxifen-inducible and conditional fashion. Analysis of these mice confirmed that mIGF-1-induced SirT1 activity is necessary to protect the heart from paraquat (PQ)-induced oxidative stress and lethality. In cultured CM, mIGF-1 increases SirT1 expression through a c-Jun NH(2)-terminal protein kinase 1 (JNK1)-dependent signaling mechanism. Thus, mIGF-1 protects the heart from oxidative stress via SirT1/JNK1 activity, suggesting new avenues for cardiac therapy during aging and heart failure.

Proatherogenic Abnormalities of Lipid Metabolism in SirT1 Transgenic Mice Are Mediated through Creb Deacetylation

Dyslipidemia and atherosclerosis are associated with reduced insulin sensitivity and diabetes, but the mechanism is unclear. Gain of function of the gene encoding deacetylase SirT1 improves insulin sensitivity and could be expected to protect against lipid abnormalities. Surprisingly, when transgenic mice overexpressing SirT1 (SirBACO) are placed on atherogenic diet, they maintain better glucose homeostasis, but develop worse lipid profiles and larger atherosclerotic lesions than controls. We show that transcription factor cAMP response element binding protein (Creb) is deacetylated in SirBACO mice. We identify Lys136 is a substrate for SirT1-dependent deacetylation that affects Creb activity by preventing its cAMP-dependent phosphorylation, leading to reduced expression of glucogenic genes and promoting hepatic lipid accumulation and secretion. Expression of constitutively acetylated Creb (K136Q) in SirBACO mice mimics Creb activation and abolishes the dyslipidemic and insulin-sensitizing effects of SirT1 gain of function. We propose that SirT1-dependent Creb deacetylation regulates the balance between glucose and lipid metabolism, integrating fasting signals.