Submit manuscript...
International Journal of
eISSN: 2573-2889

Molecular Biology: Open Access

Opinion Volume 2 Issue 2

The future of genomic medicine involves the maintenance of sirtuin 1 in global populations

Martins Ian James1,2,3

1Centre of Excellence in Alzheimer’s disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, 6027, Australia
2School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Nedlands, 6009
3Mc Cusker Alzheimer’s Research Foundation, Hollywood Medical Centre, 85 Monash Avenue, Suite 22, Nedlands, 6009, Australia

Correspondence: Martins, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, Western Australia 6027, Australia, Tel 61 863042574

Received: February 24, 2017 | Published: March 2, 2017

Citation: Ian M. The future of genomic medicine involves the maintenance of sirtuin 1 in global populations. Int J Mol Biol Open Access. 2017;2(2):42-45. DOI: 10.15406/ijmboa.2017.02.00013

Download PDF

Abstract

Genomic healthcare now requires the need for the critical assessment of novel molecular biological discoveries that may identify anti-aging genes and transcription factors that are defective in non alcoholic fatty liver disease (NAFLD), obesity, diabetes, cardiovascular disease and neurodegenerative diseases. It is estimated that 30% of the global community will be at risk for NAFLD and the future of genomics in medicine may require nutrigenomics in shaping medicine with fundamental shifts in how we define the nutritional treatment of global chronic disease. The Sirtuin 1 (Sirt 1) gene has now been identified as the gene to be defective and linked to genetic diseases, NAFLD, diabetes and neurodegenerative diseases. Bacterial lipopolysaccharide (LPS) may induce various chronic diseases and may act as a competitive inhibitor to Sirt 1 with glucose and cholesterol toxicity to various cells and tissues. Nutritional diets are required to activate Sirt 1 and improve drug response to cells with increased hepatic drug metabolism important to prevent drug induced toxicity with relevance to the global chronic disease epidemic.

Keywords: genomic, medicine, global, sirtuin 1, nutrigenomics, nafld, obesity, diabetes, bacterial, lipopolysaccharide, transcriptional, dysregulation, fibroblast growth factor 21

Opinion

Genomic medicine has become of importance to the current global chronic disease epidemic. Genomic healthcare will become of critical importance when genomic information can be used routinely to improve the health, diagnosis and treatment of all individuals.1 Genomic medicine has been used for next-generation sequencing in cancer pharmacogenomics for the diagnosis of rare disorders and determination of infectious disease outbreaks. The progress in dissecting the molecular basis of common diseases such as the role of the host microbiome, identification of drug response biomarkers and determination of hepatic drug metabolism has become important.2 The difficulty in establishing clinical validity and utility of tests to increase their awareness and promote their use for genomic healthcare now require the need for the critical assessment of novel molecular biological discoveries that include the anti-aging genes and transcription factors that become defective early in life with relevance to non alcoholic fatty liver disease (NAFLD), obesity, diabetes, cardiovascular disease and neurodegenerative diseases. In the year 2015 it is now estimated that 30% of the Western World will now progress to NAFLD and by the year 2050 if NAFLD remains untreated in the Western world the prevalence of the disease may rise to 40% of the global population.3 The future of genomics in medicine may require nutrigenomics in shaping medicine with fundamental shifts in how we define the nutritional treatment of global chronic disease,4 (Figure 1).

Figure 1 The anti-aging gene Sirt 1 is defective in obesity and diabetes with miRNAs relevant to Sirt 1 repression. Nutrigenomics is now important to genomic medicine with activation of Sirt 1/p53 interactions important to transcriptional dysregulation of cell glucose and cholesterol metabolism. Defective Sirt 1 activity in cells may be associated with insulin resistance and autoimmune disease and connected to programmed cell death in various tissues/organs. Nutritional interventions in individuals with chronic diseases may be ineffective with relevance to thermoregulation defects in individuals in the global chronic disease epidemic.

The gene-environment interaction in Western countries indicates that with urbanization5 and access to food its content may lead to induction of epigenetic alterations that are associated with lipid and glucose dyshomeostasis with increased risk for insulin resistance relevant to Type 1, Type 2 and Type 3 diabetes and obesity (Figure 1) in these countries. The gene environment interaction now identify the nuclear receptor Sirtuin 1 (Sirt 1) that regulates appetite6 and neuron proliferation7 to be involved in the induction of insulin resistance that involve alterations in nuclear receptors, micro RNA with chromatin remodelling8 that are now closely associated with global chronic disease (Figure 1). The interest in glucose metabolism has accelerated with the role of Sirt 1 and its role in the transcriptional regulation of p539 linked to p53 transcriptional regulation of caveolin 1 expression 10‒12 associated with insulin receptor transport and activity.13‒16 Sirt 1’s involvement in cholesterol transport requires the nuclear liver X receptor-ATP binding cassette transporter protein 1 (LXR-ABCA1) and Sirt 1 mediated caveolin expression involved in cholesterol metabolism in the liver and brain.4

Sirt 1 is a nicotinamide adenine dinucleotide (NAD+) dependent class III histone deacetylase (HDAC) that targets transcription factors to adapt gene expression to metabolic activity and the deacetylation of nuclear receptors indicate its critical involvement in insulin resistance.8,9 Sirt 1 is also involved in telomerase reverse transcriptase and genomic DNA repair with its involvement in telomere maintenance that maintains chromosome stability and cell proliferation.17,18 In situ hybridization analysis has localized the human Sirt1 gene to chromosome 10q21.3.19 The Sirt 1 gene has now been linked to various diseases with deletions, inversions and aberrations in chromosome 10q21.3.20‒25

Sirt 1 targets transcription factors peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha), p53, pregnane x receptor (PXR) by deacetylation to adapt gene expression to mitochondrial biogenesis with effects on metabolic activity, insulin resistance and inflammation.8 Furthermore Sirt 1/p53 interactions may regulate adipocytokines and immunometabolism that may be important to NAFLD, obesity and neurodegeneration.26 Over nutrition is associated with the repression of Sirt 1/p53 interactions and other anti-aging genes such as Klotho, p66shc (longevity protein) and FOXO1/FOXO3a6 that are now connected to autonomous diseases of the brain and liver.

Dietary fat down regulation of Sirt1contributes to reduced adiponectin expression in obesity and diabetes27 with effects on adipose tissue transformation and development of liver disease.28 Sirt 1 increases adiponectin transcription in Adipocytes by activation of forkhead transcription factorO1(Foxo) interaction with CCAAT/enhancer binding protein alpha(C/EBPalpha) to form a transcription complexat the mouse adiponectin promoter that up-regulates adiponectin gene transcription.27 Sirt1 interactions with C/EBP alpha may involve Klotho C/EBP alpha and peroxisome proliferator-activated receptor (PPAR) interactions29‒31 with their important triolein Adipocyte differentiation. Micro RNA (miR) such as miR-34a, miR-122 and miR-132 are associated with Sirt 1 repression relevant to low adipose tissue adiponectin release and the development of metabolic disease and NAFLD.8

NutritionandPPARalpha-Sirt1 expression is related to hepatic Fibro blast growth factor21 (FGF21) production important to NAFLD and diabetes.32‒37 FGF21is an important activator of Sirt1mediated release of adiponectin.38 FGF21 binds to FGF receptor and beta klotho receptor complex38‒43 and activates adipose tissue Sirt1 by increases in NAD+ and activation ofPGC1-alpha and AMP activated protein kinase (AMPK).37,44 FGF21 and its effect on thermoregulation45 may involve Sirt 1 regulation of heat shock proteins (HSP) by deacetylation of heat shock factor (HSF) via PGC1α as a critical repressor of HSF1-mediated transcriptional programs.46,47 Sirt 1 is involved in body temperature regulation of the mammalian target of rapamycin (mTOR) signaling through the tumor suppressor tuberous sclerosis complex 1 with relevance to the expression of hepatic PGC-1α and FGF21.48

Genomic medicine is delivered to patients and members of the general global community in managing their own health with interventions critical to prevent bacterial lipopolysaccharide (LPS) that are involved transactivation of p53 and repression of Sirt 1 associated with defective nuclear and mitochondria interactions and the induction of various chronic diseases,8 (Figure 2). Plasma LPS levels have increased in the developing world with LPS effects on caveolin expression and the LXR-ABCA1 pathway4 that induce hypercholesterolemia and NAFLD.49 LPS repression of Sirt 1 also involves neutralization of apolipoprotein E49 with relevance to corruption of peripheral cholesterol, alpha synuclein and amyloid beta metabolism50,51 relevant to inflammation, cardiovascular and neurodegenerative diseases.

Figure 2 Bacterial lipo polysaccharides may act as a competitive inhibitor to Sirt 1 and prevent its role in the survival of cells in many diseased tissues. LPS may induce cell membrane transformation with the induction of dyslipidemia and NAFLD. The major defect in diseased cells from the global chronic disease epidemic is the defective nuclear-mitochondria interaction with relevance of LPS to increased toxicity and autonomous organ disease.

LPS inserts itself into the cell membrane by binding to the cholesterol/sphingomylein domain with transformation of the cell membrane that involves GM1 ganglioside relevant to various chronic diseases (Figure 2).52 LPS effects on Sirt 1 repression are important to increased toxic heat shock proteins and defective thermoregulation associated with autoimmunity that involve the natural killer cells and macrophages.26,48,53 LPS induce zinc and magnesium deficiency50,54 both activators of Sirt 1with corruption of Sirt 1’s role in genomic medicine with the development of autonomous organ diseases. LPS may be referred to as a competitive inhibitor of Sirt 1’s role in the regulation of cell cholesterol and glucose metabolism critical to maintain organ/tissue survival (Figure 2).

Acknowledgements

This work was supported by grants from Edith Cowan University, the Mc Cusker Alzheimer's Research Foundation and the National Health and Medical Research Council.

Conflicts of interest

Author declares that there is no conflict of interest.

References

  1. Mattick JS, Dziadek M, Terrill B, et al. The impact of genomics on the future of medicine and health. Med J Aust. 2014;201(1):17‒20.
  2. McCarthy JJ, McLeod HL, Ginsburg GS. Genomic Medicine: A Decade of Successes, Challenges, and Opportunities. Sci Transl Med. 2013;189(5):189sr4.
  3. Martins IJ. Induction of NAFLD with Increased Risk of Obesity and Chronic Diseases in Developed Countries. Open J Endocr Metab Dis. 2014;4:90‒110.
  4. Martins IJ. Over nutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases. Int J Mol Sci. 2015;16(12):29554‒29573.
  5. Martins IJ. Increased Risk for Obesity and Diabetes with Neurodegeneration in Developing Countries. J Mol Genet Med. 2013;(S1)001:1‒8.
  6. Martins, IJ. Anti-Aging Genes Improve Appetite Regulation and Reverse Cell Senescence and Apoptosis in Global Populations. AAR. 2016;5:9‒26.
  7. Herskovits AZ, Guarente L. SIRT1 in neurodevelopment and brain senescence. Neuron. 2014;81(3):471‒483.
  8. Martins IJ. Unhealthy Nutrigenomics Diets Accelerate NAFLD and Adiposity in Global communities. J Mol Genet Med. 2015;9(1):1‒11.
  9. Martins IJ. Nutritional and Genotoxic Stress Contributes to Diabetes and Neurodegenerative Diseases such as Parkinson's and Alzheimer's Diseases. Frontiers in Clinical Drug Research -CNS and Neurological Disorders. 2015;35:158‒192.
  10. Bist A, Fielding CJ, Fielding PE. p53 regulates caveolin gene transcription, cell cholesterol, and growth by a novel mechanism. Biochemistry. 2000;39(8):1966‒1972.
  11. Galbiati F, Volonte D, Liu J, et al. Caveolin-1 expression negatively regulates cell cycle progression by inducing G0/G1 arrest via a p53/p21WAF1/Cip1-dependent mechanism. Mol Biol Cell. 2001;12(8):2229‒2244.
  12. Volonte D, Zou H, Bartholomew JN, et al. Oxidative stress-induced inhibition of Sirt1 by caveolin-1 promotes p53-dependent premature senescence and stimulates the secretion of interleukin 6 (IL-6). J Biol Chem. 2015;290(7):4202–4214.
  13. Cohen AW, Combs TP, Scherer PE, et al. Role of caveolin and caveolae in insulin signaling and diabetes. Am J Physiol Endocrinol Metab. 2003;285(6):E1151‒1160.
  14. Yamamoto M, Toya Y, Schwencke C, et al. Caveolin is an activator of insulin receptor signaling. J Biol Chem. 1998;273(41):26962‒26968.
  15. Nystrom FH, Chen H, Cong LN, et al. Caveolin-1 interacts with the insulin receptor and can differentially modulate insulin signaling in transfected Cos-7 cells and rat adipose cells. Mol Endocrinol. 1999;13(12):2013‒2024.
  16. Cohen AW, Razani B, Wang XB, et al. Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am J Physiol Cell Physiol. 2003;285(1):C222‒235.
  17. Chen H, Liu X, Zhu W, et al. SIRT1 ameliorates age-related senescence of mesenchymal stem cells via modulating telomere shelterin. Front Aging Neurosci. 2014;6:103.
  18. Palacios JA, Herranz D, De Bonis ML, et al. SIRT1 contributes to telomere maintenance and augments global homologous recombination. J Cell Biol. 2010;191(7):1299‒1313.
  19. Voelter-Mahlknecht S, Mahlknecht U. Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1. Int J Mol Med. 2006;17(1):59‒67.
  20. Kim JH, Jung SH, Bae JS, et al. Deletion variants of RABGAP1L, 10q21.3, and C4 are associated with the risk of systemic lupus erythematosus in Korean women. Arthritis Rheum. 2013;65(4):1055‒1063.
  21. Bowles KR, Gajarski R, Porter P, et al. Gene mapping of familial autosomal dominant dilated cardiomyopathy to chromosome 10q21-23. J Clin Invest. 1996;98(6):1355‒1360.
  22. Bartnik M, Nowakowska B, Derwińska K, et al. Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability. J Appl Genet. 2014;55(1):125‒144.
  23. Castermans D, Vermeesch JR, Fryns JP, et al. Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21.3 as novel candidate genes for autism. Eur J Hum Genet. 2007;15(4):422‒431.
  24. Tzschach A, Bisgaard A-M, Kirchhoff M, et al. Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11. Eur J Hum Genet. 2010;18(3):291‒295.
  25. Bradley WEC, Raelson JV, Dubois DY, et al. Hotspots of Large Rare Deletions in the Human Genome. PLoS ONE. 2010;5(2):e9401.
  26. Martins IJ. Defective Inter­play between Adipose Tissue and Immune System Induces Non Alcoholic Fatty Liver Disease. Updates Nutr Disorders Ther1. 2017;1:3.1
  27. Qiao L, Shao J. SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. J Biol Chem. 2006;281(52):39915‒39924.
  28. Westmacott A, Burke ZD, Oliver G, et al. EBPalpha and C/EBPbeta are markers of early liver development. Int J Dev Biol. 2006;50(7):653‒657.
  29. Chihara Y, Rakugi H, Ishikawa K, et al. Klotho protein promotes adipocyte differentiation. Endocrinology. 2006;147(8):3835‒3842.
  30. Jin Q, Zhang, F, Yan T, et al. C/EBPα regulates SIRT1 expression during adipogenesis. Cell Res. 2010;20:470‒479.
  31. Oka S, Alcendor R, Zhai P, et al. PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. Cell Metab. 2011;14(5):598‒611.
  32. Mäkelä J, Tselykh TV, Maiorana F, et al. Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1α in human dopaminergic neurons via Sirtuin-1. Springerplus; 2014;3:2.
  33. Lundåsen T, Hunt MC, Nilsson LM, et al. PPA Ralpha is a key regulator of hepatic FGF21. Biochem Biophys Res Commun. 2007;360(2):437‒440.
  34. Akbar H, Batistel F, Drackley JK, et al. Alterations in Hepatic FGF21, Co-Regulated Genes, and Upstream Metabolic Genes in Response to Nutrition, Ketosis and Inflammation in Peripartal Holstein Cows. PLoS ONE. 2015;10(10):e0139963.
  35. Li Y, Wong K, Giles A, et al. Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology. 2014;146(2):539‒549.
  36. Xu J, Lloyd DJ, Hale C, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes. 2009;58(1):250‒259.
  37. Lin Z, Tian H, Lam KS, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 2013;17(5):779‒789.
  38. Chau MD, Gao J, Yang Q, et al. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc Natl Acad Sci USA. 2010;107(28):12553-12558.
  39. Suzuki M, Uehara Y, Motomura-Matsuzaka K, et al. beta Klotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol Endocrinol. 2008;22(4):1006‒1014.
  40. Yie J, Wang W, Deng L, et al. Understanding the physical interactions in the FGF21/FGFR/β-Klotho complex: Structural requirements and implications in FGF21 signaling. Chem. Biol. Drug Des. 2012;79(4):398‒410.
  41. Wolf I, Levanon-Cohen S, Bose S, et al. Klotho: A tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene. 2008;27(56):7094‒7105.
  42. Piya MK, Harte AL, Chittari MV, et al. FGF21 action on human adipose tissue compromised by reduced klotho and FGFR1 expression in type 2 diabetes mellitus. Endocr Abstr. 2013;31:P179
  43. Bass J. Forever (FGF) 21. Nat Med. 2013;19(9):1090‒1092.
  44. Mäkelä J, Tselykh TV, Maiorana F, et al. Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1α in human dopaminergic neurons via Sirtuin-1. Springerplus;2014;3:2.
  45. Ni B, Farrar JS, Vaitkus JA, et al. Metabolic Effects of FGF-21: Thermoregulation and Beyond. Front Endocrinol (Lausanne). 2015;6:148.
  46. Amat R, Planavila A, Chen SL, et al. SIRT1 controls the transcription of the peroxisome proliferator-activated receptor-gamma Co-activator-1alpha (PGC-1alpha) gene in skeletal muscle through the PGC-1alpha auto regulatory loop and interaction with MyoD. J Biol Chem. 2009;284:21872‒21880.
  47. Rodgers JT, Lerin C, Gerhart-Hines Z, et al. Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett. 2008;582(1):46‒53.
  48. Martins IJ. Heat shock gene Sirtuin 1 regulates post-prandial lipid metabolism with relevance to nutrition and appetite regulation in diabetes. Int J Diab Clin Diagn. 2016;3:20.
  49. Martins IJ. LPS Regulates Apolipoprotein E and Aβ Interactions with Effects on Acute Phase Proteins and Amyloidosis. AAR. 2015;4(2):69‒77.
  50. Martins IJ. Unhealthy Diets Determine Benign or Toxic Amyloid Beta States and Promote Brain Amyloid Beta Aggregation. Austin J Clin Neurol. 2015;2(7):1060‒1066.
  51. Martins IJ. Diabetes and Cholesterol Dyshomeostasis Involve Abnormal α-Synuclein and Amyloid Beta Transport in Neurodegenerative Diseases. Austin Alzheimer’s J Parkinson’s Dis. 2015;2(1):1020‒1028.
  52. Martins IJ. Bacterial Lipopolysaccharide Change Membrane Fluidity with Relevance to Phospholipid and Amyloid Beta Dynamics in Alzheimer’s Disease. J Microb Biochem Technol. 2016;8(4):322‒324.
  53. Lee CT, Repasky EA. Opposing roles for heat and heat shock proteins in macrophage functions during inflammation: a function of cell activation state? Front Immunol. 2012;3:140.
  54. Martins IJ. Magnesium Therapy Prevents Senescence with the Reversal of Diabetes and Alzheimer’s disease. Health. 2016;8:694‒710.
Creative Commons Attribution License

©2017 Ian. This is an open access article distributed under the terms of the, which permits unrestricted use, distribution, and build upon your work non-commercially.