Single Gene Inactivation with Implications to Diabetes and Multiple Organ Dysfunction Syndrome
Ian James Martins1-3*
1Centre of Excellence in Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Australia
2School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Nedlands, 6009, Australia
3McCusker Alzheimer's Research Foundation, Hollywood Medical Centre, Nedlands, 6009, Australia
- *Corresponding Author:
- Ian Martins
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.
E-mail: [email protected]
Received date: July 20, 2017; Accepted date: July 27, 2017; Published date: August 01, 2017
Citation: Martins IJ (2017) Single Gene Inactivation with Implications to Diabetes and Multiple Organ Dysfunction Syndrome. J Clin Epigenet. 3:24. doi: 10.21767/2472-1158.100058
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.
Diet; Sirtuin 1; Suprachiasmatic nucleus; Circadian; Xenobiotic
Specific genes that are involved in epigenetics are sensitive to
nutritional regulation, oxidative stress and the development
of insulin resistance that can result from changes in cellular
chromatin structure, DNA methylation and histone modifications
with relevance to the global chronic disease epidemic [1-7].
Epigenetic modifications in specific cells such as the brain, adipose tissue and liver are more sensitive than other tissues
. Epigenetic modifications induced by unhealthy diets or
environmental xenobiotics involve the anti-aging genes 
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).
Figure 1: Nutritional diets and environmental xenobiotics
are now involved with the repression of anti-aging
genes with epigenetic alterations linked to the global
chronic disease epidemic. Circadian dyssynchrony and
immune system imbalances involve mitochondrial
apoptosis in many tissues with relevance to diabetes
and Multiple Organ Disease Syndrome (MODS).
In the developing world with urbanization and increased access
to food epigenetic and immune system alterations are associated
with increased chronic disease susceptibility. Down regulation
of anti-aging genes reduces hepatic xenobiotic (soil, air, water)
metabolism and may promote multiple organ dysfunction syndrome (MODS) [12-14]. These toxic compounds are involved
in nuclear receptor dysfunction such as the nuclear receptor
Sirtuin 1 (Sirt 1)  that determines the survival of man and
various species with relevance to toxicity to mitochondria in
neurons [15,16] and cells in peripheral tissues [17-27].
Sirt 1 Repression with Accelerated Brain
Aging and Organ Disease
The defective gene in various chronic diseases [28-38] is Sirt 1
a NAD(+)dependent class III histone deacetylase (HDAC) protein
that targets transcription factors to adapt gene expression to
metabolic activity, insulin resistance and inflammation. Interests
in Sirt 1 have increased since it may override the effects of other
anti-aging genes such as Klotho, p66Shc (longevity protein) and
Fork head box proteins (FOXO1/FOXO3a) . In adipose tissue
gene expression profiles of Klotho, p66Shc (longevity protein) and Fork head box proteins (FOXO1/FOXO3a) have been
completed and indicate down regulation of these genes are
related to mitochondrial apoptosis, adipogenesis and adipocyte
differentiation [29-38]. Sirt 1 is central to the down regulation
of the other anti-aging genes via its role as a deacetylase of the
transcription factor p53 . Sirt 1/p53 dysregulation is important
to mitochondrial apoptosis  and p53 interference has become
a key defect in biology [39-42] with relevance to MODS and the
The main types of brain cells are the glial cells (astrocytes, oligodendrocytes, and microglia) and the interaction of the glial
cell referred to as the astrocyte with the neuron are essential to
maintain neuron life span and prevent neurodegenerative disease
. Neurons in the brain with Sirt 1 repression may undergo
early programmed cell death  with altered astrocyte neuron
interactions that lead to accelerated brain aging . Sirt 1 and
its dysfunction in the brain involves the SCN and Sirt 1 repression
inactivates the SCN that is involved with appetite regulation,
body glucose control, circadian rhythm and hepatic xenobiotic
metabolism [5,46]. Xenobiotics interfere with Sirt 1’ regulation
of DNA repair [47,48] and p53 transcriptional regulation [39-42]
with relevance to interference with mitochondrial biogenesis
[4,49,50] and promotion of mitochondrial apoptosis in neurons
with effects on synaptic plasticity [51-58].
Sirt 1 activation of the non amyloidogenic α-secretase is involved
in the processing of the amyloid precursor protein (APP) to reduce
amyloid beta generation . Sirt 1 dysregulation increased
toxic amyloid beta formation associated with mitochondrial
apoptosis . SCN and its regulation of core body temperature
 has become of major interest to species survival with Sirt 1
now regarded as the heat shock gene [62-64] with temperature
regulation critical to Sirt 1 regulation of insulin resistance and
xenobiotic metabolism [5,65,66]. Sirt 1 involvement in telomere
maintenance maintains chromosome stability and its regulation of telomere length may be nullified by increased xenobiotics with
telomere length shortening [4,5,67,68].
Sirt 1 effects on p53 gene regulation supersede micro RNA
(miRNAs) regulation of p53 [69-71] with relevance to their role
in various chronic diseases [17-27]. MiRNAs such as miR-34a 
and miR-122, miR-132 [73,74] inhibit Sirt 1 and may inactivate
p53-miRNA interactions. Interference with cellular miRNA
by diet, drugs and xenobiotics are now relevant to Sirt 1/p53
dysregulation and cell apoptosis. MiRNAs may regulate Sirt 1/p53
regulation of nuclear receptors such as peroxisome proliferatoractivated
receptor-gamma co-activator (PGC-1 alpha) and
Pregnane X Receptor (PXR) with interference with xenobiotic metabolism relevant to mitochondrial biogenesis [4,5,75,76].
Other nuclear receptors such as peroxisome proliferatoractivated
receptor gamma (PPAR gamma), PPAR alpha, beta/
delta, liver X receptors (LXR)/liver receptor homolog-1 (LRH-1)
involved in energy, glucose, cholesterol, fatty acid metabolism
are regulated by Sirt 1 with connections between hepatic nutrient
and xenobiotic metabolism (PXR, CAR and xenobiotic sensing
nuclear receptor) involved in the expression of cytochrome p
450 (CYP 450) enzymes . Increased levels of xenobiotics in
the plasma and various tissues may lead to increased reactive
oxygen species associated with low Sirt1 activity [77,78] which is
associated with chronic diseases in developing countries.
SCN dysfunction in diabetes with
relevance to MODS
Insulin resistance and beta cell dysfunction has been associated
with the development of MODS [79,80]. In Type 2 diabetes more
than 150 genetic 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 . These genes are
involved in pancreatic β cell function, insulin action and glucose
metabolism in metabolic conditions. In Type 1 diabetes the HLA
class genes have been associated with Type 1 diabetes with
differences in haplotypes in ethnic groups such as Caucasians,
African, Americans, Japanese and Chinese . Sirt 1 regulation
of the MODY gene via transcription factors hepatocyte nuclear
factor 1 has been shown with evidence of genetic regulation
of liver and pancreas in Type 1 diabetes . Nutritional
dysregulation 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 hepatic xenobiotic
metabolism (NAFLD) completely inhibited in these individuals.
Sirt 1 repression induces mitophagy with the development of
MODS and may supersede the connections between diabetic
genes (Type 1 and 2) and their associated diseases (Figure 2). Sirt
1 plays an important role in the regulation fibroblast growth factor
21 [82-84] and the apelinergic pathway  with connections
to brain insulin resistance (stroke, dementia, AD) . In Type
2 diabetes the relevance of stress, anxiety and hyperphagia are
associated with defective apelinergic pathways  and severity
of diabetes (post-transcriptional defect) associated with Sirt
1-apelinergic system defects in mental disorders .
Figure 2: Nutritional regulation of Sirt 1 is important to
prevent insulin resistance and mitophagy in diabetic
individuals. Individuals with Type 3/Type 2 diabetes
have SCN defects with accelerated NAFLD and MODS
associated with hepatic xenobiotic metabolism and
Dysregulated Sirt 1 on adipocyte differentiation and senescence
involves gene expression and secretion of adiponectin with effects on the release of adipokines and cytokines that are implicated
in NAFLD and chronic diseases [88-97]. Sirt 1 interactions with
forkhead transcription factor O1 (FOXO1), C/EBP alpha may
involve Klotho C/EBP alpha and peroxisome Proliferator-Activated
Receptor (PPAR) interactions [98-103] important to mitochondrial
function and adipocyte differentiation. Furthermore miR-122
and miR-132  have been shown directly inhibit Sirt 1 and may
interfere with adipose tissue adiponectin release. FGF21 binds
to FGF receptor and beta koltho receptor complex [104-108]
and activates adipose tissue Sirt 1/p53 with interactions with
relevance to PGC1-alpha, peroxisome proliferator activated
receptor gamma, FOXO 1 [109-111] and AMP activated protein
kinase (AMPK) involved in adipocyte tissue transformation.
FGF21 and Sirt 1 are essential for liver mitochondrial function
(Figure 2) and regulate pancreas mitochondrial biogenesis and
beta cell insulin secretion .
Sirt 1 effects on hepatic cholesterol metabolism and NAFLD are
mediated via Sirt 1 and transcription factor C/EBP alpha that
regulates the transcription of the apolipoprotein B gene .
The protein kinase c-jun amino-terminal kinase 1 (JNK1) can
phosphorylate Sirt 1 with phosphorylation of Sirt 1 important
to p53 activation with relevance to NAFLD and the metabolic
syndrome . Sirt 1 and its connections to NAFLD may
involve Brd4/p53 interactions with relevance to Brd 4-P-TEFb
involvement in mitotic progression [46,114]. The control of
the adipose tissue-liver crosstalk (gene expression) by the SCN
is defective in diabetes (Type 3) and related to excess calorie
consumption or core body temperature that overrides the Sirt
1 related SCN entrainment . SCN defects are related to the
peripheral circadian clock dyssynchrony  (adipose tissueliver
cross talk) that determine Sirt 1 regulation of low adiponectin
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).
Epigenetic Modifications Involve Nitric
Oxide and Immune Dysregulation in
Induction of epigenetic alterations that determine brain
dysfunction involve Nitric Oxide (NO) homeostasis and effect the
adipose tissue-liver crosstalk with relevance to immune alterations
that determine the survival of cells in various tissues. Diabetic
individuals with defective SCN and brain-liver crosstalk involve
immune imbalances as the primary cause of MODS. In Type 3/
Type 2 individual’s reduced xenobiotic metabolism is associated
with NAFLD and the induction of MODS connected to the immune
system. Sirt 1/p53 transcriptional responses are involved in NO
metabolism [85,117-119] and immunometabolism regulated by
diet, drugs and the environment are critical to mitochondrial
apoptosis and the induction of NAFLD in the developed world.
Sirt 1 is connected to immunometabolism  and adipogenesis
disorders with adipose tissue release of adipokines, inflammatory
cytokines, heat shock proteins and natural killer cells relevant to
mitophagy in diabetes and MODS. Sirt 1 is essential to maintain
the SCN, NO homeostasis  and its dysfunction is critical to
the defective circadian rhythm of heat shock proteins [60-63]
with relation to cellular immune response [9,120]. Sirt 1 and
its regulation of autoimmune disease is central to defective
liver fat metabolism  with maintenance of Sirt 1 in adipose
tissue and the liver of critical importance to MODS. Heat/cold
stress inactivate the heat shock gene Sirt 1 [60-63] with NO
dyshomeostasis, immune system imbalances connected to
mitophagy (Figure 3) [4,5,9]. NO regulation of p53 [117-119] is
important to epigenetic regulation and Sirt 1 post-transcriptional
regulation by NO [85,121-123] involves p53/miRNA [4,124,125],
anti-aging gene p66shc [126-128], klotho [129-131], FOXO 3a
[132,133], transcription factors PGC1 alpha [132,134,135], PPAR
[136-138], LXR-ABCA1 [139,140], AMPK signalling [85,141,142],
HSP/body temperature regulation [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
epigenetics [149,150] with relevance to human health and
disease (Figure 3). The role of NO and cytochrome p450 complex
formation [151-153] has become relevant to cytochrome P450
expression in xenobiotic metabolism  with increased liver
NO  implicated in the inactivation of Sirt1/PXR’s control of
xenobiotic metabolism [4,5,154,155]. Sirt 1 and its regulation of
immunometabolism  are connected to xenobiotic metabolism
with implications to MODS and xenobiotic induced immune
alterations [156,157]. Xenobiotics may nullify Sirt 1’s role in NO
homeostasis and vasodilation in the heart  with relevance
to interference of therapeutic drugs for blood vessel dilation
. NO regulates calcium signalling in various cells [159-161]
and in the SCN alterations in cell calcium is critical to circadian
Figure 3: The heat shock gene Sirt 1 is critical 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 formation
has become relevant to inactivation of Sirt 1 posttranscriptional
regulation of PXR/cytochrome P450
expression essential to maintain hepatic xenobiotic
Lifestyle factors with Nutritional interventions may reverse Global
chronic disease Low calorie diets that upregulate Sirt 1 promote
anti-aging gene therapy, miRNA function, transcriptional factor control and interactive nuclear receptor signalling in various cells
and tissue with relevance to maintenance of immune response
and prevention 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
hepatic xenobiotic metabolism is relevant to increased mitophagy
and neurodegeneration. Nutritional diets with Sirt 1 activators
 have become important to molecular and genetic 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 regulation of immune responses and accelerated
autoimmune disease relevant to chronic disease and MODS.
Global chronic diseases involve cellular immune alterations
that lead to mitophagy in various tissues. High calorie diets are
involved with transcriptional dysregulation and defective hepatic
xenobiotic associated with immunometabolism disorders in
genetic medicine. Nutritional regulation of Sirt 1 is essential
to maintain the interplay between NO, glucose homeostasis,
immune system and various nuclear receptors, transcription
factors/signalling factors and miRNA involved in epigenetics
with relevance to human diabetes. Bacterial LPS induced Sirt
1 repression in Type 3/Type 2 diabetes induce NAFLD with
increased xenobiotic levels linked to the development of MODS
and global chronic disease in the developing world.
This work was supported by grants from Edith Cowan University,
the McCusker Alzheimer's Research Foundation and the National
Health and Medical Research Council.
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