Omega-3 Fatty Acids Upregulate SIRT1/3, Activate PGC-1Α Via Deacetylation, and Induce Nrf1 Production in 5/6 Nephrectomy Rat Model

Total Page:16

File Type:pdf, Size:1020Kb

Omega-3 Fatty Acids Upregulate SIRT1/3, Activate PGC-1Α Via Deacetylation, and Induce Nrf1 Production in 5/6 Nephrectomy Rat Model marine drugs Article Omega-3 Fatty Acids Upregulate SIRT1/3, Activate PGC-1α via Deacetylation, and Induce Nrf1 Production in 5/6 Nephrectomy Rat Model Sung Hyun Son 1,† , Su Mi Lee 2,† , Mi Hwa Lee 3, Young Ki Son 2, Seong Eun Kim 2 and Won Suk An 2,* 1 Department of Internal Medicine, BHS Han Seo Hospital, Busan 48253, Korea; [email protected] 2 Department of Internal Medicine, Dong-A University, Busan 49201, Korea; [email protected] (S.M.L.); [email protected] (Y.K.S.); [email protected] (S.E.K.) 3 Department of Anatomy and Cell Biology, Dong-A University, Busan 49201, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-51-240-2811 † These authors contributed equally to this work. Abstract: Mitochondrial dysfunction contributes to the pathogenesis of kidney injury related with cardiovascular disease. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC- 1α) protects renal tubular cells by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). AMP- activated protein kinase (pAMPK)-mediated phosphorylation and sirtuin 1/3 (SIRT1/3)-mediated deacetylation are required for PGC-1α activation. In the present study, we aimed to investigate whether omega-3 fatty acids (FAs) regulate the expression of mediators of mitochondrial biogenesis in 5/6 nephrectomy (Nx) rats. Male Sprague-Dawley rats were assigned to the following groups: sham control, Nx, and Nx treated with omega-3 FA. The expression of PGC-1α, phosphorylated PGC- Citation: Son, S.H.; Lee, S.M.; Lee, 1α (pPGC-1α), acetylated PGC-1α, and factors related to mitochondrial biogenesis was examined M.H.; Son, Y.K.; Kim, S.E.; An, W.S. through Western blot analysis. Compared to the control group, the expression of PGC-1α, pAMPK, Omega-3 Fatty Acids Upregulate SIRT1/3, Nrf1, mTOR, and Nrf2 was significantly downregulated, and that of Keap 1, acetylated SIRT1/3, Activate PGC-1α via PGC-1α, and FoxO1/3, was significantly upregulated in the Nx group. These changes in protein Deacetylation, and Induce Nrf1 expression were rescued in the omega-3 FA group. However, the expression of pPGC-1α was similar Production in 5/6 Nephrectomy Rat among the three groups. Omega-3 FAs may involve mitochondrial biogenesis by upregulating Model. Mar. Drugs 2021, 19, 182. Nrf1 and Nrf2. This protective mechanism might be attributed to the increased expression and https://doi.org/10.3390/md19040182 deacetylation of PGC-1α, which was triggered by SIRT1/3. Academic Editor: Keywords: peroxisome proliferator-activated receptor gamma coactivator-1 alpha; nuclear respira- Constantina Nasopoulou tory factor 1; nuclear factor erythroid 2-related factor 2; sirtuin 1; sirtuin 3; omega-3 fatty acid Received: 19 March 2021 Accepted: 23 March 2021 Published: 26 March 2021 1. Introduction Publisher’s Note: MDPI stays neutral Kidneys are involved in regulating several functions, including various metabolic with regard to jurisdictional claims in pathways, water and electrolyte balance, blood pressure control, and production of several published maps and institutional affil- hormones. As these functions consume enormous energy, kidneys are rich in mitochon- iations. dria [1]. Mitochondria can adapt to different metabolic conditions via regulating mecha- nistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK)-mediated nutrient sensing pathways to maintain healthy mitochondrial population [2]. Among the studies on mitochondria, to date, there are only a few studies on mitochon- Copyright: © 2021 by the authors. drial biogenesis. Most studies related to mitochondrial biogenesis are based on non-renal Licensee MDPI, Basel, Switzerland. tissue [3,4], and studies on kidneys are mainly related to acute kidney injury (AKI) animal This article is an open access article models, proximal tubular cells, and diabetic nephropathy [5–7]. Although mitochondrial distributed under the terms and biogenesis may link to pathogenesis of mitochondrial dysfunction in non-diabetic chronic conditions of the Creative Commons kidney disease (CKD), research on this topic is also very limited. CKD and mitochondrial Attribution (CC BY) license (https:// biogenesis are related to cardiovascular disease [8,9]. Improving mitochondrial biogenesis creativecommons.org/licenses/by/ may be beneficial for cardioprotection in CKD. 4.0/). Mar. Drugs 2021, 19, 182. https://doi.org/10.3390/md19040182 https://www.mdpi.com/journal/marinedrugs Mar. Drugs 2021, 19, x FOR PEER REVIEW 2 of 10 Mar. Drugs 2021, 19, 182 mitochondrial biogenesis are related to cardiovascular disease [8,9]. Improving mitochon-2 of 10 drial biogenesis may be beneficial for cardioprotection in CKD. A study indicating that omega-3 fatty acids (FAs) facilitate the biogenesis of mito- chondriaA study was indicating conducted that using omega-3 non-kidney fatty acidstissues (FAs) [3,10]. facilitate A recent the study biogenesis demonstrated of mito- a chondriapromising was role conducted of omega-3 using FAs non-kidneyin mitochondria tissuesl biogenesis [3,10]. A in recent animal study models demonstrated with cardi- aovascular promising and role neurodegenerative of omega-3 FAs in diseases mitochondrial [11]. Therefore, biogenesis in the in animalpresent models study, we with aimed car- diovascularto investigate and mitochondrial neurodegenerative biogenesis diseases in kidneys [11]. Therefore,of 5/6 nephrectomy in the present (Nx) rats. study, Addi- we aimedtionally, to investigatewe evaluated mitochondrial the effect of biogenesisomega-3 FAs in kidneyson mitochondrial of 5/6 nephrectomy biogenesis (Nx)using rats. this Additionally,model. we evaluated the effect of omega-3 FAs on mitochondrial biogenesis using this model. 2. Results 2.2.1. Results Changes in Kidney Function and Histological Findings 2.1. Changes in Kidney Function and Histological Findings Compared to the control group, blood urea nitrogen (BUN) level in the Nx and Nx treatedCompared with omega-3 to the FA control groups group, were blood significan ureatly nitrogen increased (BUN) (control level group in the 17.7 Nx ± and 1.5, Nx Nx treatedgroup 77.7 with ± omega-3 28.4, and FA Nx groups with omega-3 were significantly FA group increased63.9 ± 17.0 (control mg/dL, group p = 0.007). 17.7 ±Although1.5, Nx groupthere 77.7was ±no28.4, significant and Nx withdifference omega-3 between FA group the 63.9 Nx ±and17.0 Nx mg/dL, treatedp = with 0.007). omega-3 Although FA theregroups, was BUN no significant levels were difference numerically between lower the Nxin the and Nx Nx treated treated with omega-3omega-3 FAFA groups, group. BUNThe serum levels werecreatinine numerically (sCr) level lower among in the the Nx thr treatedee groups with was omega-3 similar FA to group. that of TheBUN serum (con- creatininetrol group, (sCr) 0.4 ± level0.0; Nx among group, the 1.3 three ± 0.6; groups omega-3 was FA, similar 1.0 ± 0.3 to thatmg/dL; of BUN p = 0.008). (control Compared group, 0.4 ± 0.0; Nx group, 1.3 ± 0.6; omega-3 FA, 1.0 ± 0.3 mg/dL; p = 0.008). Compared to the to the control group, severe tubular dilatation and atrophy were observed using PAS control group, severe tubular dilatation and atrophy were observed using PAS staining staining in the Nx group (Supplementary Figure S1). Furthermore, the results showed that in the Nx group (Supplementary Figure S1). Furthermore, the results showed that the Nx the Nx treated with omega-3 FA group exhibited less tubulointerstitial changes than the treated with omega-3 FA group exhibited less tubulointerstitial changes than the Nx group. Nx group. The renal function and histological changes in the three groups have already The renal function and histological changes in the three groups have already been reported been reported in a previous study [12]. in a previous study [12]. 2.2.2.2. ChangesChanges inin FactorsFactors RelatedRelated toto MitochondrialMitochondrial BiogenesisBiogenesis 2.2.1.2.2.1. Nrf1Nrf1 andand Nrf2Nrf2 ExpressionExpression ComparedCompared toto the the control control group, group, the the Nx Nx group group showed showed significantly significantly decreased decreased expres- ex- sionpression level level of nuclear of nuclear respiratory respiratory factor factor 1 (Nrf1) 1 (Nrf1) and nuclear and nuclear factor erythroidfactor erythroid 2-related 2-related factor 2factor (Nrf2). 2 (Nrf2). However, However, in the Nx in treatedthe Nx treated with omega-3 with omega-3 FA group, FA the group, expression the expression level of Nrf1level andof Nrf1 Nrf2 and was Nrf2 significantly was significantly increased increased compared compared to the Nx to group, the Nx but group, did not but reach did not the levelreach ofthe control level of group control (Figure group1, Supplementary(Figure 1, Supplemen Figuretary S2). Figure These S2). results These were results also foundwere also in Nrf1found mRNA in Nrf1 quantitative mRNA quantitative real-time PCRreal-time analysis PCR (Supplementary analysis (Supplementary Figure S3). Figure S3). Figure 1. Expressions of (A) Nrf1 and (B) Nrf2 (n = 6/group). Decreased Nrf 1 and Nrf2 expressions Figure 1. Expressions of (A) Nrf1 and (B) Nrf2 (n = 6/group). Decreased Nrf 1 and Nrf2 expres- of 5/6 nephrectomy group were improved by omega-3 FA supplementation. * p value < 0.05 (mean sions of 5/6 nephrectomy group were improved by omega-3 FA supplementation. * p value < 0.05 a values(meanare values significantly are significantly different different from control). from control).p value <a p 0.05 value (mean < 0.05 values (mean are values significantly are signifi- different fromcantly the different Nx group). from the Nx group). 2.2.2. Changes in PGC-1α Expression and Its Activity The expression of peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC-1α) in the Nx group was significantly decreased compared to the control group. The Nx treated with omega-3 FA group showed significantly increased PGC-1α Mar. Drugs 2021, 19, x FOR PEER REVIEW 3 of 10 2.2.2.
Recommended publications
  • T-Cell Protein Tyrosine Phosphatase Attenuates STAT3 and Insulin
    ORIGINAL ARTICLE T-Cell Protein Tyrosine Phosphatase Attenuates STAT3 and Insulin Signaling in the Liver to Regulate Gluconeogenesis Atsushi Fukushima,1 Kim Loh,1 Sandra Galic,1 Barbara Fam,2 Ben Shields,1 Florian Wiede,1 Michel L. Tremblay,3 Matthew J. Watt,4 Sofianos Andrikopoulos,2 and Tony Tiganis1 OBJECTIVE—Insulin-induced phosphatidylinositol 3-kinase (PI3K)/Akt signaling and interleukin-6 (IL-6)-instigated JAK/ STAT3-signaling pathways in the liver inhibit the expression of ype 2 diabetes has reached epidemic propor- gluconeogenic genes to decrease hepatic glucose output. The tions, afflicting roughly 170 million people world- insulin receptor (IR) and JAK1 tyrosine kinases and STAT3 can wide. Although the underlying genetic causes serve as direct substrates for the T-cell protein tyrosine phos- Tand the associated pathologic symptoms are phatase (TCPTP). Homozygous TCPTP-deficiency results in peri- heterogenous, a common feature is high blood glucose due natal lethality prohibiting any informative assessment of to peripheral insulin resistance. Circulating insulin re- TCPTP’s role in glucose homeostasis. Here we have used leased from ␤-cells in the pancreas serves to lower blood Ptpn2ϩ/Ϫ mice to investigate TCPTP’s function in glucose glucose by triggering the translocation of the facilitative homeostasis. GLUT4 to the plasma membrane in muscle and adipose RESEARCH DESIGN AND METHODS—We analyzed insulin tissue (1). Insulin also acts in the liver to promote glycogen sensitivity and gluconeogenesis in chow versus high-fat–fed synthesis and lipogenesis and to suppress hepatic glucose (HFF) Ptpn2ϩ/Ϫ and Ptpn2ϩ/ϩ mice and insulin and IL-6 production (HGP) by inhibiting gluconeogenesis and gly- signaling and gluconeogenic gene expression in Ptpn2ϩ/Ϫ and cogenolysis (1).
    [Show full text]
  • Sirt7 Promotes Adipogenesis in the Mouse by Inhibiting Autocatalytic
    Sirt7 promotes adipogenesis in the mouse by inhibiting PNAS PLUS autocatalytic activation of Sirt1 Jian Fanga,1, Alessandro Iannia,1, Christian Smolkaa,b, Olesya Vakhrushevaa,c, Hendrik Noltea,d, Marcus Krügera,d, Astrid Wietelmanna, Nicolas G. Simonete, Juan M. Adrian-Segarraa, Alejandro Vaqueroe, Thomas Brauna,2, and Eva Bobera,2 aDepartment of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany; bMedizin III Kardiologie und Angiologie, Universitätsklinikum Freiburg, D-79106 Freiburg, Germany; cDepartment of Medicine, Hematology/Oncology, Goethe University, D-60595 Frankfurt am Main, Germany; dInstitute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), D-50931 Köln, Germany; and eCancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain Edited by C. Ronald Kahn, Section of Integrative Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, and approved August 23, 2017 (received for review April 26, 2017) Sirtuins (Sirt1–Sirt7) are NAD+-dependent protein deacetylases/ adipogenesis and accumulation of lipids in 3T3-L1 adipocytes by ADP ribosyltransferases, which play decisive roles in chromatin deacetylation of FOXO1, which represses PPARγ (10). The role of silencing, cell cycle regulation, cellular differentiation, and metab- Sirt6 in the regulation of adipogenic differentiation is less clear olism. Different sirtuins control similar cellular processes, suggest- although it is known that Sirt6 knockout (KO) mice suffer from ing a coordinated mode of action but information about potential reduced adipose tissue stores, while Sirt6 overexpressing mice cross-regulatory interactions within the sirtuin family is still lim- are protected against high-fat diet-induced obesity (11, 12).
    [Show full text]
  • A Review of the Recent Advances Made with SIRT6 and Its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets
    biomolecules Review A Review of the Recent Advances Made with SIRT6 and its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets Rubayat Islam Khan †, Saif Shahriar Rahman Nirzhor † and Raushanara Akter * Department of Pharmacy, BRAC University, 1212 Dhaka, Bangladesh; [email protected] (R.I.K.); [email protected] (S.S.R.N.) * Correspondence: [email protected]; Tel.: +880-179-8321-273 † These authors contributed equally to this work. Received: 10 June 2018; Accepted: 26 June 2018; Published: 29 June 2018 Abstract: Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide+ (NAD+) dependent enzyme and stress response protein that has sparked the curiosity of many researchers in different branches of the biomedical sciences. A unique member of the known Sirtuin family, SIRT6 has several different functions in multiple different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses, and more. Only in recent times, however, did the potential usefulness of SIRT6 come to light as we learned more about its biochemical activity, regulation, biological roles, and structure Frye (2000). Even until very recently, SIRT6 was known more for chromatin signaling but, being a nascent topic of study, more information has been ascertained and its potential involvement in major human diseases including diabetes, cancer, neurodegenerative diseases, and heart disease. It is pivotal to explore the mechanistic workings
    [Show full text]
  • Targeting the Gastrointestinal Tract to Treat Type 2 Diabetes
    230 3 P V BAUER and F A DUCA Gut treatment for diabetes 230:3 R95–R113 Review Targeting the gastrointestinal tract to treat type 2 diabetes Correspondence should be addressed 1,2 and 1 Paige V Bauer Frank A Duca to F A Duca 1Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, ON, Canada Email 2Department of Physiology, University of Toronto, Toronto, ON, Canada frank.duca@uhnres. utoronto.ca Abstract The rising global rates of type 2 diabetes and obesity present a significant economic and Key Words social burden, underscoring the importance for effective and safe therapeutic options. f gut The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 f metformin diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight f gut sensing the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, f gut microbiota recent evidence suggests that the gut plays a prominent role in the ability of metformin f bile acids to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. Endocrinology A better understanding of these pathways will lay the groundwork for novel of gut-targeted antidiabetic therapies, some of which have already shown initial promise. Journal of Endocrinology (2016) 230, R95–R113 Journal Introduction The incidence of type 2 diabetes has more than doubled Interestingly, this is not the only evidence for a since 1980, with over 382 million affected individuals therapeutic role of the gut in diabetes treatment.
    [Show full text]
  • The Sirtuin Family's Role in Aging and Age-Associated Pathologies
    The sirtuin family’s role in aging and age-associated pathologies Jessica A. Hall, … , Yoonjin Lee, Pere Puigserver J Clin Invest. 2013;123(3):973-979. https://doi.org/10.1172/JCI64094. Review Series The 7 mammalian sirtuin proteins compose a protective cavalry of enzymes that can be invoked by cells to aid in the defense against a vast array of stressors. The pathologies associated with aging, such as metabolic syndrome, neurodegeneration, and cancer, are either caused by or exacerbated by a lifetime of chronic stress. As such, the activation of sirtuin proteins could provide a therapeutic approach to buffer against chronic stress and ameliorate age- related decline. Here we review experimental evidence both for and against this proposal, as well as the implications that isoform-specific sirtuin activation may have for healthy aging in humans. Find the latest version: https://jci.me/64094/pdf Review series The sirtuin family’s role in aging and age-associated pathologies Jessica A. Hall, John E. Dominy, Yoonjin Lee, and Pere Puigserver Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. The 7 mammalian sirtuin proteins compose a protective cavalry of enzymes that can be invoked by cells to aid in the defense against a vast array of stressors. The pathologies associated with aging, such as metabolic syndrome, neuro- degeneration, and cancer, are either caused by or exacerbated by a lifetime of chronic stress. As such, the activation of sirtuin proteins could provide a therapeutic approach to buffer against chronic stress and ameliorate age-related decline.
    [Show full text]
  • Analysis of Sirtuin 1 Expression Reveals a Molecular Explanation of IL-2–Mediated Reversal of T-Cell Tolerance
    Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2–mediated reversal of T-cell tolerance Beixue Gao, Qingfei Kong, Kyeorda Kemp, Yuan-Si Zhao, and Deyu Fang1 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Edited by Arthur Weiss, University of California, San Francisco, CA, and approved December 8, 2011 (received for review November 9, 2011) The type III histone deacetylase sirtuin 1 (Sirt1) is a suppressor of both ably allowing accelerated T-cell proliferation and differentiation. innate and adoptive immune responses. We have recently found that Because Sirt1 is required for maintaining and IL-2 reverses T-cell Sirt1 expression is highly induced in anergic T cells. However, the peripheral tolerance, our findings here provide a possible explana- transcriptional program to regulate Sirt1 expression in T cells remains tion about the IL-2–mediated switch from anergy to activation. uncharacterized. Here we report that the early responsive genes 2 and 3, which can be up-regulated by T-cell receptor-mediated activa- Results tion of nuclear factor of activated T-cell transcription factors and are Differential Sirt1 Expression in Mouse Primary T Cells. We have re- involved in peripheral T-cell tolerance, bind to the sirt1 promoter to cently reported that sirt1 gene transcription is induced by TCR- transcript sirt1 mRNA. In addition, the forkhead transcription factor, mediated anergic signaling, and this increased Sirt1 expression is FoxO3a, interacts with early responsive genes 2/3 on the sirt1 pro- required to maintain peripheral T-cell tolerance (9). To further moter to synergistically regulate Sirt1 expression.
    [Show full text]
  • The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function
    International Journal of Molecular Sciences Article The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function João S. Teodoro 1,2,* , João A. Amorim 1,3,4 , Ivo F. Machado 1,2 , Ana C. Castela 1,2, Clemens Steegborn 5, David A. Sinclair 4,6, Anabela P. Rolo 1,2 and Carlos M. Palmeira 1,2,* 1 Center for Neurosciences and Cell Biology of the University of Coimbra, 3004-504 Coimbra, Portugal; [email protected] (J.A.A.); [email protected] (I.F.M.); [email protected] (A.C.C.); [email protected] (A.P.R.) 2 Department of Life Sciences of the University of Coimbra, 3000-456 Coimbra, Portugal 3 IIIUC—Institute of Interdisciplinary Research of the University of Coimbra, 3030-789 Coimbra, Portugal 4 Department of Genetics, Blavatnik Institute, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA; [email protected] 5 Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany; [email protected] 6 Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney 2052, Australia * Correspondence: [email protected] (J.S.T.); [email protected] (C.M.P.); Tel.: +351-239-240-700 (J.S.T. & C.M.P.) Received: 13 May 2020; Accepted: 5 July 2020; Published: 11 July 2020 Abstract: Hepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction.
    [Show full text]
  • Sirtuins Transduce Stacs Signals Through Steroid Hormone Receptors Henry K
    www.nature.com/scientificreports OPEN Sirtuins transduce STACs signals through steroid hormone receptors Henry K. Bayele SIRT1 protects against several complex metabolic and ageing-related diseases (MARDs), and is therefore considered a polypill target to improve healthy ageing. Although dietary sirtuin- activating compounds (dSTACs) including resveratrol are promising drug candidates, their clinical application has been frustrated by an imprecise understanding of how their signals are transduced into increased healthspan. Recent work indicates that SIRT1 and orthologous sirtuins coactivate the oestrogen receptor/ER and the worm steroid receptor DAF-12. Here they are further shown to ligand-independently transduce dSTACs signals through these receptors. While some dSTACs elicit ER subtype-selectivity in the presence of hormone, most synergize with 17β-oestradiol and dafachronic acid respectively to increase ER and DAF-12 coactivation by the sirtuins. These data suggest that dSTACs functionally mimic gonadal steroid hormones, enabling sirtuins to transduce the cognate signals through a conserved endocrine pathway. Interestingly, resveratrol non-monotonically modulates sirtuin signalling, suggesting that it may induce hormesis, i.e. “less is more”. Together, the fndings suggest that dSTACs may be informational molecules that use exploitative mimicry to modulate sirtuin signalling through steroid receptors. Hence dSTACs’ intrinsic oestrogenicity may underlie their proven ability to impart the health benefts of oestradiol, and also provides a mechanistic insight into how they extend healthspan or protect against MARDs. Among the seven human sirtuins, SIRT1 (silent information regulator 2 homologue 1) has received the most attention because of its many roles including gene regulation, genomic stability and energy metabolism1,2. SIRT1 is also of enormous interest as a viable drug target because it protects against several conditions including obesity, type 2 diabetes, cancer and cardiovascular and neurodegenerative diseases3,4.
    [Show full text]
  • Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1
    Rapid Temporal Control of Foxp3 Protein Degradation by Sirtuin-1 Jorg van Loosdregt1,2, Diede Brunen1,3, Veerle Fleskens1,3, Cornelieke E. G. M. Pals1,3, Eric W. F. Lam4, Paul J. Coffer1,2,3* 1 Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands, 2 Center for Molecular & Cellular Intervention, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands, 3 Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands, 4 CR-UK Labs and Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom Abstract Maintenance of Foxp3 protein expression in regulatory T cells (Treg) is crucial for a balanced immune response. We have previously demonstrated that Foxp3 protein stability can be regulated through acetylation, however the specific mechanisms underlying this observation remain unclear. Here we demonstrate that SIRT1 a member of the lysine deacetylase Sirtuin (SIRT) family, but not the related SIRTs 2–7, co-localize with Foxp3 in the nucleus. Ectopic expression of SIRT1, but not SIRTs 2–7 results in decreased Foxp3 acetylation, while conversely inhibition of endogenous SIRT activity increased Foxp3 acetylation. We show that SIRT1 inhibition decreases Foxp3 poly-ubiquitination, thereby increasing Foxp3 protein levels. Co-transfection of SIRT1 with Foxp3 results in increased Foxp3 proteasomal degradation, while SIRT inhibition increases FOXP3 transcriptional activity in human Treg. Taken together, these data support a central role for SIRT1 in the regulation of Foxp3 protein levels and thereby in regulation of Treg suppressive capacity. Pharmacological modulation of SIRT1 activity in Treg may therefore provide a novel therapeutic strategy for controlling immune responses.
    [Show full text]
  • A Novel Sirtuin 2 (SIRT2) Inhibitor with P53-Dependent Pro-Apoptotic
    THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 289, NO. 8, pp. 5208–5216, February 21, 2014 © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. A Novel Sirtuin 2 (SIRT2) Inhibitor with p53-dependent Pro-apoptotic Activity in Non-small Cell Lung Cancer*□S Received for publication, August 19, 2013, and in revised form, December 17, 2013 Published, JBC Papers in Press, December 30, 2013, DOI 10.1074/jbc.M113.487736 Gesine Hoffmann‡**, Frank Breitenbücher§, Martin Schuler§¶, and Ann E. Ehrenhofer-Murray‡**1 From the ‡Zentrum fu¨r Medizinische Biotechnologie, Universität Duisburg-Essen, 45117 Essen, Germany, the §Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum, Universitätsklinikum Essen, 45147 Essen, Germany, the ¶German Cancer Consortium (DKTK) , 69120 Heidelberg, Germany, and the **Humboldt-Universität zu Berlin, Institut fu¨r Biologie, Abteilung Molekulare Zellbiologie, 10115 Berlin, Germany Background: Pharmacological inhibition of the NADϩ-dependent deacetylase SIRT2 holds promise for cancer therapy by preventing deacetylation and inactivation of p53. Results: We identified two novel SIRT2 inhibitors that induce apoptosis in a p53-dependent fashion and activate three p53 target genes. Conclusion: Small-molecule inhibition of SIRT2 activates p53-dependent apoptosis in cancer cells. Significance: The compounds reported here are promising lead candidates for use in cancer treatment. ؉ Sirtuin 2 (SIRT2) is an NAD -dependent protein deacetylase activity (3–5). Sirtuin enzymes have received widespread atten- whose targets include histone H4 lysine 16, p53, and ␣-tubulin. tion over the last few years due to their diverse physiological Because deacetylation of p53 regulates its effect on apoptosis, roles in metabolism, aging, and age-related human disorders pharmacological inhibition of SIRT2-dependent p53 deacetyla- (6–8).
    [Show full text]
  • Activation of the AMPK/Sirt1 Pathway by a Leucine
    METABOLISM CLINICAL AND EXPERIMENTAL 65 (2016) 1679– 1691 Available online at www.sciencedirect.com Metabolism www.metabolismjournal.com Activation of the AMPK/Sirt1 pathway by a leucine–metformin combination increases insulin sensitivity in skeletal muscle, and stimulates glucose and lipid metabolism and increases life span in Caenorhabditis elegans Jheelam Banerjee⁎, Antje Bruckbauer, Michael B. Zemel NuSirt BioPharma Inc., 11020 Solway School Road, Knoxville, TN 37931, USA ARTICLE INFO ABSTRACT Article history: Background. We have previously shown leucine (Leu) to activate Sirt1 by lowering its KM for Received 28 January 2016 NAD+, thereby amplifying the effects of other sirtuin activators and improving insulin Accepted 29 June 2016 sensitivity. Metformin (Met) converges on this pathway both indirectly (via AMPK) and by direct activation of Sirt1, and we recently found Leu to synergize with Met to improve insulin Keywords: sensitivity and glycemic control while achieving ~80% dose-reduction in diet-induced obese AMPK mice. Accordingly, we sought here to define the mechanism of this interaction. Sirt1 Methods. Muscle cells C2C12 and liver cells HepG2 were used to test the effect of Met–Leu on Insulin sensitivity Sirt1 activation. Caenorhabditis elegans was used for glucose utilization and life span studies. Leucine Results. Leu (0.5 mmol/L) + Met (50–100 μmol/L) synergistically activated Sirt1 (p < 0.001) at + Metformin low (≤100 μmol/L) NAD levels while Met exerted no independent effect. This was associated with an increase in AMPK and ACC, phosphorylation, and increased fatty acid oxidation, which was prevented by AMPK or Sirt inhibition or silencing. Met–Leu also increased P-IRS1/IRS1 and P-AKT/AKT and in insulin-independent glucose disposal in myotubes (~50%, p < 0.002) evident within 30 min as well as a 60% reduction in insulin EC50.
    [Show full text]
  • Sirtuins: Novel Targets for Metabolic Disease Peter J Elliott* & Michael Jirousek
    371 Current Opinion in Investigational Drugs 2008 9(4):371-378 © The Thomson Corporation ISSN 1472-4472 Sirtuins: Novel targets for metabolic disease Peter J Elliott* & Michael Jirousek Address Sirtris Pharmaceuticals Inc, 200 Technology Square, Cambridge, MA 02139, USA Email: [email protected] *To whom correspondence should be addressed Sirtuins represent a novel family of enzymes that are collectively well situated to help regulate nutrient sensing and utilization, metabolic rate and ultimately metabolic disease. Activation of one of these enzymes, SIRT1, leads to enhanced activity of multiple proteins, including peroxisome-proliferator activated receptor coactivator-1α (PGC-1α), which helps to mediate some of the in vitro and in vivo effects of sirtuins. As such, enhanced SIRT1 activity decreases glucose levels, improves insulin sensitivity, increases mitochondrial number and function, decreases adiposity, improves exercise tolerance and potentially lowers body weight. SRT-501 is a proprietary formulation of resveratrol with improved bioavailability. As such, SRT-501 represents the first in a novel class of SIRT1 activators that has proven to be safe and well-tolerated in humans. Clinical trials in type 2 diabetic patients are currently underway. Keywords Calorie restriction, diabetes, mitochondria, PGC-1α, resveratrol, SIRT1, SRT501 Introduction their uniqueness provides opportunities for their modulation The identification of mammalian sirtuins (SIRTs; silent and the subsequent development of selective agents information regulator transcript) with close homology to Sir2 designed for specific therapeutic targets [11]. from yeast is a recent discovery, which has ignited the field of caloric restriction (CR) and metabolic control [1,2]. CR A vast majority of publications on sirtuins and metabolic is one of the best known methods for extending a healthy disease have focused on SIRT1.
    [Show full text]