Single Gene Inactivation with Implications to Diabetes and Multiple Organ Dysfunction Syndrome

Abstract

Nutritional and environmental epigenetics are involved with the repression of
anti-aging genes that are linked to the chronic disease epidemic. Unhealthy diets
inactivate the calorie sensitive gene Sirtuin 1 (Sirt 1) involved in epigenetic processes
that promote immune system alterations, mitochondrial apoptosis, Non-alcoholic
Fatty Liver Disease (NAFLD), diabetes and Nitric Oxide (NO) modification with
relevance to core body temperature involved with appetite regulation, glucose
homeostasis and hepatic xenobiotic metabolism. The interplay between NO and
epigenetics has attracted interest with relevance to autoimmune disease and
mitophagy that has become of critical concern to diabetes and the development
of MODS. Future research involved with nutritional research and the maintenance
of Sirt 1 transcriptional control is critical to the prevention of MODS that is linked
to the immune system and insulin resistance. In the developing world bacterial
lipopolysaccharides a critical repressor of Sirt 1 is now involved with NAFLD and
various organ diseases relevant to tissue accumulation of xenobiotics from various
environments with relevance to MODS and the global chronic disease epidemic.

Full text

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Research Article
2017
Vol. 3 No. 3: 24
DOI: 10.21767/2472-1158.100058
1
© Under License of Creative Commons Attribution 3.0 License | This article is available in: hp://www.clinical-epigenecs.imedpub.com/
Journal of Clinical Epigenetics
ISSN 2472-1158
Ian James Martins1-3*
1 Centre of Excellence in Alzheimer’s
Disease Research and Care, School of
Medical and Health Sciences, Edith
Cowan University, Australia
2 School of Psychiatry and Clinical
Neurosciences, The University of
Western Australia, Nedlands, 6009,
Australia
3 McCusker Alzheimer's Research
Foundaon, Hollywood Medical
Centre, Nedlands, 6009, Australia
*Corresponding author: Ian Marns
 i.marns@ecu.edu.au
Centre of Excellence in Alzheimer’s Disease
Research and Care, School of Medical and
Health Sciences, Edith Cowan University,
270 Joondalup Drive, Joondalup, Western
Australia 6027, Australia.
Tel: +61863042574
Citaon: Marns IJ (2017) Single Gene
Inacvaon with Implicaons to Diabetes
and Mulple Organ Dysfuncon Syndrome. J
Clin Epigenet. Vol. 3 No. 3:24
Introducon
Specic genes that are involved in epigenecs are sensive to
nutrional regulaon, oxidave stress and the development
of insulin resistance that can result from changes in cellular
chroman structure, DNA methylaon and histone modicaons
with relevance to the global chronic disease epidemic [1-7].
Epigenec modifications in specific cells such as the brain,
adipose tissue and liver are more sensitive than other tissues
[4]. Epigenetic modifications induced by unhealthy diets or
environmental xenobiotics involve the anti-aging genes [8]
that alter gene expression in the Suprachiasmatic Nucleus
(SCN) in the brain [4,5] with effects on peripheral lipid
metabolism and energy expenditure that involve the adipose
tissue and liver with immune alterations [9-11] that determine
the survival of cells in various tissues (Figure 1).
In the developing world with urbanizaon and increased access
to food epigenec and immune system alteraons are associated
with increased chronic disease suscepbility. Down regulaon
of an-aging genes reduces hepac xenobioc (soil, air, water)
metabolism and may promote mulple organ dysfuncon
Received: July 20, 2017; Accepted: July 27, 2017; Published: August 01, 2017
Single Gene Inacvaon with
Implicaons to Diabetes and Mulple
Organ Dysfuncon Syndrome
Abstract
Nutrional and environmental epigenecs are involved with the repression of
an-aging genes that are linked to the chronic disease epidemic. Unhealthy diets
inacvate the calorie sensive gene Sirtuin 1 (Sirt 1) involved in epigenec processes
that promote immune system alteraons, mitochondrial apoptosis, Non-alcoholic
Fay Liver Disease (NAFLD), diabetes and Nitric Oxide (NO) modicaon with
relevance to core body temperature involved with appete regulaon, glucose
homeostasis and hepac xenobioc metabolism. The interplay between NO and
epigenecs has aracted interest with relevance to autoimmune disease and
mitophagy that has become of crical concern to diabetes and the development
of MODS. Future research involved with nutrional research and the maintenance
of Sirt 1 transcriponal control is crical to the prevenon of MODS that is linked
to the immune system and insulin resistance. In the developing world bacterial
lipopolysaccharides a crical repressor of Sirt 1 is now involved with NAFLD and
various organ diseases relevant to ssue accumulaon of xenobiocs from various
environments with relevance to MODS and the global chronic disease epidemic.
Keywords: Diet; Sirtuin 1; Suprachiasmac nucleus; Circadian; Xenobioc
syndrome (MODS) [12-14]. These toxic compounds are involved
in nuclear receptor dysfuncon such as the nuclear receptor
Sirtuin 1 (Sirt 1) [5] that determines the survival of man and
various species with relevance to toxicity to mitochondria in
neurons [15,16] and cells in peripheral ssues [17-27].
Sirt 1 Repression with Accelerated Brain
Aging and Organ Disease
The defecve gene in various chronic diseases [28-38] is Sirt 1
a NAD(+)dependent class III histone deacetylase (HDAC) protein
that targets transcripon factors to adapt gene expression to
metabolic acvity, insulin resistance and inammaon. Interests
in Sirt 1 have increased since it may override the eects of other
an-aging genes such as Klotho, p66Shc (longevity protein) and
Fork head box proteins (FOXO1/FOXO3a) [8]. In adipose ssue
gene expression proles of Klotho, p66Shc (longevity protein)

2This article is available in: hp://www.clinical-epigenecs.imedpub.com/
Vol. 3 No. 3: 24
2017
Journal of Clinical Epigenetics
ISSN 2472-1158
and Fork head box proteins (FOXO1/FOXO3a) have been
completed and indicate down regulaon of these genes are
related to mitochondrial apoptosis, adipogenesis and adipocyte
dierenaon [29-38]. Sirt 1 is central to the down regulaon
of the other an-aging genes via its role as a deacetylase of the
transcripon factor p53 [8]. Sirt 1/p53 dysregulaon is important
to mitochondrial apoptosis [4] and p53 interference has become
a key defect in biology [39-42] with relevance to MODS and the
diabetes epidemic.
The main types of brain cells are the glial cells (astrocytes,
oligodendrocytes, and microglia) and the interacon of the glial
cell referred to as the astrocyte with the neuron are essenal to
maintain neuron life span and prevent neurodegenerave disease
[43]. Neurons in the brain with Sirt 1 repression may undergo
early programmed cell death [44] with altered astrocyte neuron
interacons that lead to accelerated brain aging [45]. Sirt 1 and
its dysfuncon in the brain involves the SCN and Sirt 1 repression
inacvates the SCN that is involved with appete regulaon,
body glucose control, circadian rhythm and hepac xenobioc
metabolism [5,46]. Xenobiocs interfere with Sirt 1’ regulaon
of DNA repair [47,48] and p53 transcriponal regulaon [39-42]
with relevance to interference with mitochondrial biogenesis
[4,49,50] and promoon of mitochondrial apoptosis in neurons
with eects on synapc plascity [51-58].
Sirt 1 acvaon of the non amyloidogenic α-secretase is involved
in the processing of the amyloid precursor protein (APP) to reduce
amyloid beta generaon [59]. Sirt 1 dysregulaon increased
toxic amyloid beta formaon associated with mitochondrial
apoptosis [60]. SCN and its regulaon of core body temperature
[61] has become of major interest to species survival with Sirt 1
now regarded as the heat shock gene [62-64] with temperature
regulaon crical to Sirt 1 regulaon of insulin resistance and
xenobioc metabolism [5,65,66]. Sirt 1 involvement in telomere
maintenance maintains chromosome stability and its regulaon
of telomere length may be nullied by increased xenobiocs with
telomere length shortening [4,5,67,68].
Sirt 1 eects on p53 gene regulaon supersede micro RNA
(miRNAs) regulaon of p53 [69-71] with relevance to their role
in various chronic diseases [17-27]. MiRNAs such as miR-34a [72]
and miR-122, miR-132 [73,74] inhibit Sirt 1 and may inacvate
p53-miRNA interacons. Interference with cellular miRNA
by diet, drugs and xenobiocs are now relevant to Sirt 1/p53
dysregulaon and cell apoptosis. MiRNAs may regulate Sirt 1/p53
regulaon of nuclear receptors such as peroxisome proliferator-
acvated receptor-gamma co-acvator (PGC-1 alpha) and
Pregnane X Receptor (PXR) with interference with xenobioc
metabolism relevant to mitochondrial biogenesis [4,5,75,76].
Other nuclear receptors such as peroxisome proliferator-
acvated receptor gamma (PPAR gamma), PPAR alpha, beta/
delta, liver X receptors (LXR)/liver receptor homolog-1 (LRH-1)
involved in energy, glucose, cholesterol, fay acid metabolism
are regulated by Sirt 1 with connecons between hepac nutrient
and xenobioc metabolism (PXR, CAR and xenobioc sensing
nuclear receptor) involved in the expression of cytochrome p
450 (CYP 450) enzymes [5]. Increased levels of xenobiocs in
the plasma and various ssues may lead to increased reacve
oxygen species associated with low Sirt1 acvity [77,78] which is
associated with chronic diseases in developing countries.
SCN dysfuncon in diabetes with
relevance to MODS
Insulin resistance and beta cell dysfuncon has been associated
with the development of MODS [79,80]. In Type 2 diabetes more
than 150 genec loci are associated with the development of
diabetes and 50 candidate genes have shown to play a major
part in the development of the disease [81]. These genes are
involved in pancreac β cell funcon, insulin acon and glucose
metabolism in metabolic condions. In Type 1 diabetes the HLA
class genes have been associated with Type 1 diabetes with
dierences in haplotypes in ethnic groups such as Caucasians,
African, Americans, Japanese and Chinese [46]. Sirt 1 regulaon
of the MODY gene via transcripon factors hepatocyte nuclear
factor 1 has been shown with evidence of genec regulaon
of liver and pancreas in Type 1 diabetes [81]. Nutrional
dysregulaon of Sirt1 and the SCN may now involve Type 1,
Type 2 and Type 3 diabetes (Figure 2) [63,82] and induce MODS
that involves accelerated organ diseases with hepac xenobioc
metabolism (NAFLD) completely inhibited in these individuals.
Sirt 1 repression induces mitophagy with the development of
MODS and may supersede the connecons between diabec
genes (Type 1 and 2) and their associated diseases (Figure 2). Sirt
1 plays an important role in the regulaon broblast growth factor
21 [82-84] and the apelinergic pathway [85] with connecons
to brain insulin resistance (stroke, demena, AD) [86]. In Type
2 diabetes the relevance of stress, anxiety and hyperphagia are
associated with defecve apelinergic pathways [85] and severity
of diabetes (post-transcriponal defect) associated with Sirt
1-apelinergic system defects in mental disorders [87].
Dysregulated Sirt 1 on adipocyte dierenaon and senescence
involves gene expression and secreon of adiponecn with eects
ANTI-AGING GENES
BRAIN
ADIPOCYTE-LIVER INTERATION
IMMUNE SYSTEM
PANCREAS
HEART
VASCULATURE
KIDNEY
LUNGS
Figure 1 Nutrional diets and environmental xenobiocs
are now involved with the repression of an-aging
genes with epigenec alteraons linked to the global
chronic disease epidemic. Circadian dyssynchrony and
immune system imbalances involve mitochondrial
apoptosis in many ssues with relevance to diabetes
and Mulple Organ Disease Syndrome (MODS).

3
© Under License of Creative Commons Attribution 3.0 License
2017
Vol. 3 No. 3: 24
Journal of Clinical Epigenetics
ISSN 2472-1158
on the release of adipokines and cytokines that are implicated
in NAFLD and chronic diseases [88-97]. Sirt 1 interacons with
forkhead transcripon factor O1 (FOXO1), C/EBP alpha may
involve Klotho C/EBP alpha and peroxisome Proliferator-Acvated
Receptor (PPAR) interacons [98-103] important to mitochondrial
funcon and adipocyte dierenaon. Furthermore miR-122
and miR-132 [4] have been shown directly inhibit Sirt 1 and may
interfere with adipose ssue adiponecn release. FGF21 binds
to FGF receptor and beta koltho receptor complex [104-108]
and acvates adipose ssue Sirt 1/p53 with interacons with
relevance to PGC1-alpha, peroxisome proliferator acvated
receptor gamma, FOXO 1 [109-111] and AMP acvated protein
kinase (AMPK) involved in adipocyte ssue transformaon.
FGF21 and Sirt 1 are essenal for liver mitochondrial funcon
(Figure 2) and regulate pancreas mitochondrial biogenesis and
beta cell insulin secreon [112].
Sirt 1 eects on hepac cholesterol metabolism and NAFLD are
mediated via Sirt 1 and transcripon factor C/EBP alpha that
regulates the transcripon of the apolipoprotein B gene [113].
The protein kinase c-jun amino-terminal kinase 1 (JNK1) can
phosphorylate Sirt 1 with phosphorylaon of Sirt 1 important
to p53 acvaon with relevance to NAFLD and the metabolic
syndrome [46]. Sirt 1 and its connecons to NAFLD may
involve Brd4/p53 interacons with relevance to Brd 4-P-TEFb
involvement in mitoc progression [46,114]. The control of
the adipose ssue-liver crosstalk (gene expression) by the SCN
is defecve in diabetes (Type 3) and related to excess calorie
consumpon or core body temperature that overrides the Sirt
1 related SCN entrainment [61]. SCN defects are related to the
peripheral circadian clock dyssynchrony [115] (adipose ssue-
liver cross talk) that determine Sirt 1 regulaon of low adiponecn
and melatonin levels involved in the metabolic syndrome, NAFLD
and reverse cholesterol transport [61,83,116] with relevance to
diabetes and the severity of MODS (Figure 2).
Epigenec Modicaons Involve Nitric
Oxide and Immune Dysregulaon in
Diabetes
Inducon of epigenec alteraons that determine brain
dysfuncon involve Nitric Oxide (NO) homeostasis and eect the
adipose ssue-liver crosstalk with relevance to immune alteraons
that determine the survival of cells in various ssues. Diabec
individuals with defecve SCN and brain-liver crosstalk involve
immune imbalances as the primary cause of MODS. In Type 3/
Type 2 individual’s reduced xenobioc metabolism is associated
with NAFLD and the inducon of MODS connected to the immune
system. Sirt 1/p53 transcriponal responses are involved in NO
metabolism [85,117-119] and immunometabolism regulated by
diet, drugs and the environment are crical to mitochondrial
apoptosis and the inducon of NAFLD in the developed world.
Sirt 1 is connected to immunometabolism [9] and adipogenesis
disorders with adipose ssue release of adipokines, inammatory
cytokines, heat shock proteins and natural killer cells relevant to
mitophagy in diabetes and MODS. Sirt 1 is essenal to maintain
the SCN, NO homeostasis [85] and its dysfuncon is crical to
the defecve circadian rhythm of heat shock proteins [60-63]
with relaon to cellular immune response [9,120]. Sirt 1 and
its regulaon of autoimmune disease is central to defecve
liver fat metabolism [9] with maintenance of Sirt 1 in adipose
ssue and the liver of crical importance to MODS. Heat/cold
stress inacvate the heat shock gene Sirt 1 [60-63] with NO
dyshomeostasis, immune system imbalances connected to
mitophagy (Figure 3) [4,5,9]. NO regulaon of p53 [117-119] is
important to epigenec regulaon and Sirt 1 post-transcriponal
regulaon by NO [85,121-123] involves p53/miRNA [4,124,125],
an-aging gene p66shc [126-128], klotho [129-131], FOXO 3a
[132,133], transcripon factors PGC1 alpha [132,134,135], PPAR
[136-138], LXR-ABCA1 [139,140], AMPK signalling [85,141,142],
HSP/body temperature regulaon [143-146] and glucose
homeostasis [147,148]. The importance of Sirt 1 and the immune
response is now consistent with its interplay between NO and
epigenecs [149,150] with relevance to human health and
disease (Figure 3). The role of NO and cytochrome p450 complex
formaon [151-153] has become relevant to cytochrome P450
expression in xenobioc metabolism [5] with increased liver
NO [85] implicated in the inacvaon of Sirt1/PXR’s control of
xenobioc metabolism [4,5,154,155]. Sirt 1 and its regulaon of
immunometabolism [9] are connected to xenobioc metabolism
with implicaons to MODS and xenobioc induced immune
alteraons [156,157]. Xenobiocs may nullify Sirt 1’s role in NO
homeostasis and vasodilaon in the heart [85] with relevance
to interference of therapeuc drugs for blood vessel dilaon
[158]. NO regulates calcium signalling in various cells [159-161]
and in the SCN alteraons in cell calcium is crical to circadian
dyssynchrony [162].
Lifestyle factors with Nutrional intervenons may reverse Global
chronic disease Low calorie diets that upregulate Sirt 1 promote
an-aging gene therapy, miRNA funcon, transcriponal factor
SIRTUIN 1
REPRESSION
MODS
SCN DEFECT AND NAFLD
TYPE 1
DIABETES TYPE 2
DIABETES
TYPE 3
DIABETES
SIRTUIN 1
TYPE 3/TYPE 2
DIABETES
Figure 2 Nutrional regulaon of Sirt 1 is important to
prevent insulin resistance and mitophagy in diabec
individuals. Individuals with Type 3/Type 2 diabetes
have SCN defects with accelerated NAFLD and MODS
associated with hepac xenobioc metabolism and
mitophagy.

4This article is available in: hp://www.clinical-epigenecs.imedpub.com/
Vol. 3 No. 3: 24
2017
Journal of Clinical Epigenetics
ISSN 2472-1158
p53/miRNA, Anti-aging genes (p66she, klotho, FOXO 3a)
LXR-ABCA1), Signalling JNK1 or AMPK pathway
Transcription factors, Nuclear receptors (PGCI alpha, PPAR,
NATURAL
KILLER CELLS
MITOPHAGY
XENOBIOTIC METABOLISM
CORE BODY TEMPERATURE
INSULIN RESISTANCE
SIRTUIN 1
EPIGENETICS DIABETES
NITRIC OXIDE
CALCIUM SIGNALLING
EPIGENETICS
IMMUNE
SYSTEM
MODS
Figure 3 The heat shock gene Sirt 1 is crical to NO
homeostasis, immune system imbalances connected
to mitophagy. NO, nuclear receptor signalling and the
immune response is now connected to MODS. The
role of NO and cytochrome p450 complex formaon
has become relevant to inacvaon of Sirt 1 post-
transcriponal regulaon of PXR/cytochrome P450
expression essenal to maintain hepac xenobioc
metabolism.
control and interacve nuclear receptor signalling in various cells
and ssue with relevance to maintenance of immune response
and prevenon of autoimmune disease that may be connected
to global chronic disease and the development of MODS (Figure
3). Bacterial LPS is involved with NAFLD and interference with
hepac xenobioc metabolism is relevant to increased mitophagy
and neurodegeneraon. Nutrional diets with Sirt 1 acvators
[162] have become important to molecular and genec medicine
with relevance to immune disturbances and mitophagy [9,60]
in diabetes and MODS (Figure 3). Anxiety, stress and heat/cold
stress may induce heat shock protein-mitophagy [9,60,61,63]
relevant to brain disease. Sirt 1 inhibitors [162,163] may interfere
with dietary regulaon of immune responses and accelerated
autoimmune disease relevant to chronic disease and MODS.
Conclusion
Global chronic diseases involve cellular immune alteraons
that lead to mitophagy in various ssues. High calorie diets are
involved with transcriponal dysregulaon and defecve hepac
xenobioc associated with immunometabolism disorders in
genec medicine. Nutrional regulaon of Sirt 1 is essenal
to maintain the interplay between NO, glucose homeostasis,
immune system and various nuclear receptors, transcripon
factors/signalling factors and miRNA involved in epigenecs
with relevance to human diabetes. Bacterial LPS induced Sirt
1 repression in Type 3/Type 2 diabetes induce NAFLD with
increased xenobioc levels linked to the development of MODS
and global chronic disease in the developing world.
Acknowledgements
This work was supported by grants from Edith Cowan University,
the McCusker Alzheimer's Research Foundaon and the Naonal
Health and Medical Research Council.
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