Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 21, 2007
Contents
Src Inhibitors and Angiogenesis Pp. 2118-2128
S. Schenone, F. Manetti and M. Botta
[Abstract]
Targeting Vascular Cell Migration as a Strategy for
Blocking Angiogenesis: The Central Role of Focal Adhesion
Protein Tyrosine Kinase Family Pp. 2129-2145
A. Angelucci and M. Bologna
[Abstract]
New Potential Pharmaceutical Targets of Metabolic
Syndrome
Executive Editors: Gianluca Iacobellis and Giuseppe Barbaro
Editorial Pp. 2146-2147
Metabolic Syndrome and Adipose Tissue: New Clinical
Aspects and Therapeutic Targets Pp. 2148-2168
C.V. Iannucci, D. Capoccia, M. Calabria and F. Leonetti
[Abstract]
Visceral and Subcutaneous Adiposity: Are Both Potential
Therapeutic Targets for Tackling the Metabolic Syndrome?
Pp. 2169-2175
A. Rodríguez, V. Catalán, J. Gómez-Ambrosi
and G. Frühbeck
[Abstract]
Homo obesus: A Metabotrophin-Deficient Species.
Pharmacology and Nutrition Insight Pp. 2176-2179
G.N. Chaldakov, M. Fiore, A.B. Tonchev, D. Dimitrov, R.
Pancheva, G. Rancic and L. Aloe
[Abstract]
Epicardial Adipose Tissue As New Cardio-Metabolic
Risk Marker and Potential Therapeutic Target in the Metabolic
Syndrome Pp. 2180-2184
G. Iacobellis and A.M. Sharma
[Abstract]
Dual Modulation of Vascular Function by Perivascular
Adipose Tissue and Its Potential Correlation with Adiposity/Lipoatrophy
Related Vascular Dysfunction Pp. 2185-2192
Y.-J. Gao
[Abstract]
Non-Alcoholic Fatty Liver Disease in the Metabolic
Syndrome Pp. 2193-2198
G. Palasciano, A. Moschetta, V.O. Palmieri, I. Grattagliano,
G. Iacobellis and P. Portincasa
[Abstract]
Targeting the Liver in the Metabolic Syndrome: Evidence
from Animal Models Pp. 2199-2207
M. Petruzzelli, G.L. Sasso, P. Portincasa, G. Palasciano
and A. Moschetta
[Abstract]
Visceral Fat as Target of Highly Active Antiretroviral
Therapy Associated Metabolic Syndrome Pp. 2208-2213
G. Barbaro
[Abstract]
Abstracts
[Back to top]
Src Inhibitors and Angiogenesis
S. Schenone, F. Manetti and M. Botta
Angiogenesis is a tightly regulated process that leads to
the formation of new blood vessels in limited physiological
conditions, and can also occur under pathological situations
as retinopathies, arthritis, endometriosis and cancer. Enhanced
angiogenesis is present in tumors that need new blood capillaries
to grow, remove metabolic waste and transport the cells to
locations distal to the primary tumor, facilitating metastasis
formation. For these reasons, blockade of angiogenesis is
an attractive approach for the treatment of both solid and
haematological malignancies. Antiangiogenic therapy should
be less toxic in comparison with conventional treatments such
as chemotherapy, being angiogenesis a process relatively restricted
to the growing tumor. The Src family of tyrosine kinases has
been implicated in the intracellular signaling cascade that
acts downstream of cell surface receptors to elicit different
cellular functions, including growth, proliferation, adhesion
and motility. Src kinases are frequently activated in human
malignancies, causing tumor progression, metastasis formation
and deregulating expression of proangiogenic molecules. This
review reports several studies performed by different authors
demonstrating the involvement of Src tyrosine kinases in angiogenesis
by regulating different signalling pathways. Moreover, we
report selective Src inhibitors for which a direct involvement
with angiogenesis has been demonstrated, even if every Src
inhibitor could potentially possesses also antiangiogenic
properties. Biological data, structures and mechanisms of
action of selected molecules, in terms of Src protein-inhibitor
interactions, are also reported.
[Back to top]
Targeting Vascular Cell Migration as a Strategy for
Blocking Angiogenesis: The Central Role of Focal Adhesion
Protein Tyrosine Kinase Family
A. Angelucci and M. Bologna
The formation of capillary-like structures during angiogenesis
requires a series of well-orchestrated cellular events allowing
endothelial cells and pericytes to migrate into the perivascular
space. The proper activation of the migratory machinery in
these cells is fine controlled by the presence of angiogenic
challenges and by the interactions with extracellular matrix.
The two members of the focal adhesion protein tyrosine kinases
(FA-PTKs), FAK and PYK2, play a central role in modulating
endothelial and vascular smooth muscle cells migration confirming
the well consolidated observations in other migrating cell
types. However accumulating data reveal that FAK and PYK2
are involved in several cell processes including cell proliferation
and survival. FAK, once localized to focal adhesions, is thought
to be one of the principal effectors in linking signals initiated
by integrins and growth factor receptors to cytoskeleton,
thus controlling migration. Although more obscure, and differently
regulated, the function of PYK2 seems to be similar to that
of FAK, but restricted to few cell types, including vasculature
forming cells. FAK and PYK2 exert a primary role as adaptor
proteins able to recruit, with high turnover, several proteins
which in turn, through their docking domains and tyrosine
kinase activity, determine both the turnover in focal adhesion
assembly and the specificity of downstream signaling. The
characterization of functional interactions of FA-PTKs may
provide new potential therapeutic targets in order to control
vascular pathological processes including angiogenesis.
[Back to top]
Editorial: New Potential Pharmaceutical
Targets of Metabolic Syndrome
Affirming that excess fat can be an unfavourable medical condition
is definitively not an observation of great originality. In
fact, in 400 BC, Hippocrates astutely observed that “sudden
death was more common in those who are naturally fat than
in the lean” [1].
By the contrast, the concept of targeting the adipose tissue
and internal organs with increased fat content during pharmaceutical
or lifestyle intervention is of great novelty. If the reduction
of excess fat is still a therapeutic goal in improving a poor
cardio-metabolic profile, new insights suggest the potential
of improving the effectiveness of therapeutic intervention
through the adiposity, not only against. In fact, there is
now a compelling need of emerging therapeutic strategies targeted
to the adipose tissue.
The reason for the growing scientific interest into the fat
is the widely-accepted acknowledgement that adipose tissue
is not a silent organ, but a very active source of multiple
bioactive cytokines, called adipokines. The adipocyte, mini-organ
within this neglected organ, sends outputs (adipokines) and
accept inputs (nuclear receptors). The adipose tissue communicates
with almost all other organs through endocrine, paracrine
and also autocrine interactions. Hence, both systemic and
local regulations of internal organs’ function and morphology
have been recently attributed to the adipose tissue. Fat tissue
is also a potential great responder, by the presence of multiple
receptors that can be modulated, stimulated or inhibited by
drugs with different mechanisms of action and therapeutic
purposes. Of additional and supportive note is the fact that
the adipose tissue can now be clinically measured and quantified
by simple, accurate and reliable diagnostic tools. Both biological
and clinical characteristics of the adipose tissue seem to
warrant a successful development of new therapeutic strategies.
The concept and importance of proximity of adipose tissue
to the organs is also intriguing. Intuitively, the visceral
adipose tissue has been evoked as the most desirable therapeutic
target. In fact, great interest has been recently focused
on the visceral adiposity, namely the fat depots that surround
the internal organs. The evidences supporting the visceral
adiposity as independent cardio-metabolic risk factor are
rapidly emerging. A body of studies suggest that the increased
fat, particularly the visceral fat, may play a significant
role in the development of the metabolic syndrome, a cluster
of diseases apparently independent, but actually linked by
common pathogenic key factors.
In this Current Pharmaceutical Design issue, leading
experts in clinical and bio-molecular aspects of adiposity,
and its relationship with metabolic syndrome, addressed a
topic of growing and exciting interest, as well as the potential
use of different adipose tissue depots and organs as therapeutic
targets. A systematic and detailed overview of basic and clinical
aspects of adiposity-related diseases and an extremely up-to-date
of the potential within targeting adipose tissue and fatty
organs, are provided in this Current Pharmaceutical Design
issue.
Leonetti et al. [2] introduced the concept of metabolic
syndrome, with its diagnostic aspects still controversial
and under continue evolution. They extensively discussed the
importance of regional fat distribution rather total adiposity
in cardiovascular risk stratification. Waist circumference
and imaging diagnostics have been evaluated as traditional
and new markers of visceral adiposity. Great attention is
focused on reinforce the notion that reductions in visceral
adipose tissue should be a primary aim of strategies designed
to reduce health risks associated with metabolic syndrome.
Human adipose tissues are not only located in different anatomic
compartments, but differ for embryological origin, bio-molecular
properties, and therefore different therapeutic use.
Adipose tissue depot-specific differences in lipolysis and
adipokines production have been clearly addressed by Frubeck
and al [3]. Targeting the visceral fat seems to be a successful
therapeutic strategy to prevent insulin resistance and glucose
intolerance. Pharmacological modulation of visceral adipose
tissue function including up-regulation of anti-inflammatory
and protective cytokines, as well as adiponectin, and down-regulation
of pro-inflammatory factors, such as Interleukin 6 (IL-6),
Tumor Necrosis Factor-alpha??resistin or leptin, might represent
promising strategies for the treatment of the metabolic syndrome.
The role of the new adipokines visfatin and retinol binding
protein 4 is still at its beginning . Thiazolidinediones (TZD)
and fibrates have been shown to increase adiponectin expression
in human visceral adipose tissue, through activation of peroxisome
proliferator-activated receptors (PPARs), respectively PPARα
and PPARγ.
Hence, anti-diabetic and lipid-lowering drugs seem to work
as pharmaceuticals targeted to visceral adipose tissue. However,
Frubeck et al. indicated also subcutaneous fat as
potential therapeutic target in metabolic syndrome. In fact,
α2-adrenoceptor
antagonists could be considered a plausible strategy to optimize
lipid mobilization in subjects with prevalent subcutaneous
adiposity that are following low-calorie diets combined with
exercise regimens.
Chaldakov et al. [4] nicely discussed new concepts
of adipobiology and its application for development of new
drugs. New pharmaceuticals, classified as nutraceuticals and
xenohormetics, targeting transcriptional, secretory and/or
signaling pathways of metabotrophins, particularly adiponectin,
and nerve growth factor, brain-derived neurotrophic factor,
and IL-10, might be new tools for the pharmacological treatment
of subjects with metabolic syndrome.
Iacobellis and Sharma [5] proposed the epicardial adipose
tissue as new cardiovascular risk marker and potential therapeutic
target. This small visceral fat, previously neglected or rapidly
removed from the cardiac surgeons, seems to play as principal
actor, for its proximity to the heart. Paradoxically, a double
role, unfavourable and protective, has been also attributed
to the cardiac fat. Given that epicardial fat reflects visceral
adiposity, its echocardiographic measurement has been proposed
as therapeutic target and also marker of drug effectiveness
in subjects in treatment with medications able to modulate
and affect adipose tissue, particularly the visceral depots.
Intuitively, TZD, fibrates, Angiotensin type 1 Receptor Blockers,
and anti-obesity medication, as well as sibutramine, orlistat
and rimonabant could be targeted to the echocardiographic
epicardial fat thickness. The fact that echocardiography is
now routinely performed in subjects with metabolic syndrome
suggests the great potential of this diagnostic tool.
As observed for the epicardial adipose tissue, great interest
is into the perivascular fat, punctually elaborated by Gao
[6]. Although metabolic syndrome and increased adiposity are
associated with atherosclerosis, a potential active role of
adipose tissue in modulating vascular function has been only
recently explored. The modulation of vascular function by
perivascular adipose tissue seems to be composed of a balance
between relaxation and contraction factors. Perivascular fat
can be easily measured, quantified and targeted during weight-loss
interventional approaches or pharmaceutical treatment.
In a clinical scenario that includes increased adiposity and
high cardio-metabolic risk, the liver play undoubtedly a crucial
role. Non-alcoholic fatty liver disease (NAFLD) is often associated
with features of the metabolic syndrome, carrying an increased
risk to develop non-alcoholic steatohepatitis (NASH), the
inflammatory form of liver steatosis.
Palasciano et al. [7] and Moschetta et al.
[8] focused on this topic from the clinical and experimental
perspective. The liver rises as the leading organ in the maintenance
of metabolic fitness; it serves as the first relay station
for processing dietary information and encloses the whole
biochemical machinery for both glucose and lipid storage and
disposal. Targeted therapeutic actions seem to be necessary
for the management of liver dysfunction in course of metabolic
syndrome. Palasciano et al. suggested that the pharmacological
arsenal is wide and includes traditional and new, promising
drugs. Pharmaceuticals directly or indirectly targeted to
the liver and hepatic fat, as well as weight reducing agents,
insulin sensitizers, cytoprotective compounds, antihypertensive
and lipid lowering agents have been proposed and discussed.
Improvement of insulin sensitivty, anti-oxidant effect, induction
of increased protective or decreased pro-inflammatory adipokines
production have been all evoked to explain the potential therapeutic
effects on both NAFLD and NASH.
Moschetta et al. extensively reviewed the evidences and the
perspectives from animal models supporting the role of the
nuclear receptors, expressed in the liver and adipose tissue,
as targets of new drugs. The lesson from experimental and
also clinical data suggest that the liver should be the preferential
target of the fibrates, PPARα
agonists. TZDs, PPARγ
agonists, are currently used with significant clinical improvement
of insulin resistance and glucose tolerance, although a direct
role of PPARγ
activity in the liver is still controversial. PPARδ
agonists seem to be promising candidates for the clinical
management of metabolic syndrome. Pharmacological targeting
of Farnesoid X Receptor pathway has been suggested also for
the treatment of hypertriglyceridemia and fatty liver disease,
through inhibition of Sterol Regulatory Element–Binding
protein-1c activity. PPARα
and PPARγ
agonists, currently available in the market, and future FXR
and PPARδ
agonists, seem to provide new and promising therapeutic strategies
in metabolic syndrome and NAFLD
Finally, Barbaro [9] desribed a new and emerging clinical
entity, with great potential and still open diagnostic and
therapetic approaches. In fact the introduction of highly
active antiretroviral therapy (HAART) for the treatment of
human immunodeficiency virus (HIV) infection provided several
beneficial effects, but also some metabolic abnormalities.
HAART is associated with the development of HAART-associated
metabolic syndrome, characterized by lipodystrohy, adipose
tissue redistribution and increased visceral adiposity. We
know that increased visceral fat, as observed in HIV-infected
patients receiving HAART, is associated with higher cardiometabolic
risk and accelerated atherosclerosis . Although the mechanisms
underlying its development are still unclear, it has been
suggested that HAART may interfere with adipocyte differentiation
and production of adipokines. Barbaro correctly suggested
that a better understanding of the molecular mechanisms responsible
for this syndrome will lead to the discovery of new drugs
that will reduce the incidence of lipodystrophy and related
metabolic complications in HIV-infected patients receiving
HAART. Also in this clinical condition, echocardiographic
assessment of epicardial and perivascular fat may have the
potential to be simple and reliable markers of increased visceral
adiposity in HIV-infected patients with HAART-associated metabolic
syndrome.
In conclusion, this Current Pharmaceutical Design
issue is not only a prestigious space for eminent scientists,
leaders in the field of adiposity, but an unique opportunity
to discuss perspectives and plan future potential therapeutic
strategies targeted to the fat and fatty organs, that clearly
may open new pathways for the treatment of metabolic syndrome.
References
[1] Chadwick J, Mann WN. The Medical Works of Hippocrates.
Springfield, IL: Charles C Thomas Co,1950.
[2] Iannucci CV, Capoccia D, Calabria M, Leonetti F Metabolic
syndrome and adipose tissue: new clinical aspects and therapeutic
targets. Curr Pharm Des 2007; 13(21): 2148-2168.
[3] Rodríguez A, Catalán V, Ambrosi JG, Frühbeck
G. Visceral and Subcutaneous Adiposity: Are Both Potential
Therapeutic Targets for Tackling the Metabolic Syndrome? Curr
Pharm Des 2007; 13(21): 2169-2175.
[4] Chaldakov GN, Fiore M, Tonchev AB, Dimitrov D, Pancheva
R, Rancic G, Aloe L Homo Obesus: A Metabotrophin-deficient
Species. Pharmacology and Nutrition Insight. Curr Pharm Des
2007; 13(21): 2176-2179.
[5] Iacobellis G, Sharma AM. Epicardial adipose tissue as
new cardio-metabolic risk marker and potential therapeutic
target in the metabolic sindrome. Curr Pharm Des 2007; 13(21):
2180-2184.
[6] Gao YL Dual modulation of vascular function by perivascular
adipose tissue and its potential correlation with adiposity/lipoatrophy-related
vascular dysfunction. Curr Pharm Des 2007; 13(21): 2185-2192.
[7] Palasciano G, Moschetta A, Calmieri VO, Grattagliano I,
Iacobellis G, Portincasa P. Non-Alcoholic Fatty Liver Disease
In The Metabolic Sindrome. Curr Pharm Des 2007; 13(21): 2193-2198.
[8] Petruzzelli M, Lo Sasso G, Portincasa P, Palasciano G,
Moschetta A. Targeting the liver in the metabolic syndrome:
evidence from animal models. Curr Pharm Des 2007; 13(21):
2199-2207.
[9] Barbaro G. Visceral fat as target of highly active antiretroviral
therapy-associated metabolic sindrome. Curr Pharm Des 2007;
13(21): 2208-2213.
Gianluca Iacobellis
Department of Medicine
Division of Endocrinology
McMaster University Hamilton
Ontario
Canada
Giuseppe Barbaro
Cardiology Unit
Department of Medical Pathophysiology
University “La Sapienza”
Rome
Italy
[Back to top]
Metabolic Syndrome and Adipose Tissue: New Clinical
Aspects and Therapeutic Targets
C.V. Iannucci, D. Capoccia, M. Calabria and F. Leonetti
The metabolic syndrome is a long-term process, explained by
the interaction of genetic and environmental factors, that
starts early in life and is involved in the pathophysiology
of a large percentage of cases with type 2 diabetes and atherosclerosis.
A number of clinical studies have demonstrated the importance
of fat distribution and especially the contribution of visceral
fat accumulation to the development of metabolic disorders.
Visceral adipose tissue can be studied through different imaging
techniques. The accumulation of visceral adipose tissue, as
opposed to subcutaneous fat, increases the risk of developing
metabolic disease and cardiovascular diseases (CVD).
Visceral adipocytes secrete a variety of cytokines known as
adipocytokines suggesting that adipose tissue is an endocrine
organ that may affect the function of other organs.
Weight loss, particularly a reduction in waist circumference,
improves insulin sensitivity, lipid profile, and serum adipocytokines,
reducing the risk of developing chronic disease and CVD.
Waist circumference is a required component of metabolic syndrome
under the International Diabetes Federation (IDF) criteria,
rather than an optional component as used by other previous
classifications. Studies have shown that using a lower waist
circumference threshold within the context of metabolic syndrome
increases the prevalence, but decreases the risk of mortality
and type 2 diabetes.
It is possible that waist circumference acts as a marker for
other risk factors. These findings reinforce the notion that
reductions in visceral adipose tissue should be a primary
aim of strategies designed to reduce health risks associated
with metabolic syndrome.
[Back to top]
Visceral and Subcutaneous Adiposity: Are Both Potential
Therapeutic Targets for Tackling the Metabolic Syndrome?
A. Rodríguez, V. Catalán, J. Gómez-Ambrosi
and G. Frühbeck
The metabolic syndrome represents a constellation of co-morbidities
that include central adiposity, insulin resistance, dyslipidemia
and hypertension, which results from an elevated prevalence
of obesity. An increased abdominal adiposity is observed in
upper-body obesity with preferential accumulation of fat in
the visceral depot, which renders these individuals more prone
to metabolic and cardiovascular problems. The pathophysiology
of the metabolic syndrome seems to be closely associated to
an elevated efflux of free fatty acids from the visceral fat
compartment and a dysregulation of the expression of adipose
tissue-derived factors (also termed “adipokines”).
Weight reduction and increased physical activity represent
the main approach to tackle the “diabesity” epidemic.
Nonetheless, taking advantage of the different biochemical
and molecular characteristics of visceral and subcutaneous
adipose tissue may open up novel pharmacological strategies
to combat the metabolic and cardiovascular derangements accompanying
the metabolic syndrome.
[Back to top]
Homo obesus: A Metabotrophin-Deficient Species.
Pharmacology and Nutrition Insight
G.N. Chaldakov, M. Fiore, A.B. Tonchev, D. Dimitrov, R.
Pancheva, G. Rancic and L. Aloe
In most countries the prevalence of obesity now exceeds 15%,
the figure used by the World Health Organization to define
the critical threshold for intervention in nutritional epidemics.
Here we describe Homo obesus (man the obese) as a
recent phenotypic expression of Homo sapiens. Specifically,
we classified Homo obesus as a species deficient
of metabotrophic factors (metabotrophins), including endogenous
proteins, which play essential role in the maintenance of
glucose, lipid, energy and vascular homeostasis, and also
improve metabolism-related processes such as inflammation
and wound healing. Here we propose that pharmaceuticals, nutraceuticals
and xenohormetics targeting transcriptional, secretory and/or
signaling pathways of metabotrophins, particularly adiponectin,
nerve growth factor, brain-derived neurotrophic factor, interleukin-10,
and sirtuins, might be new tools for therapy of Homo obesus.
Brief comment is also given to (i) exogenous metabotrophic
agents represented by various classes of drugs, and (ii) adiponutrigenomics
of lifspan.
[Back to top]
Epicardial Adipose Tissue As New Cardio-Metabolic
Risk Marker and Potential Therapeutic Target in the Metabolic
Syndrome
G. Iacobellis and A.M. Sharma
Increased visceral adiposity, is an emerging cardiovascular
risk factor. There is now a compelling need to quantify visceral
adipose tissue not only for diagnostic purposes, but also
for therapeutic interventions with weight reduction drugs
or pharmaceuticals targeted to adipose tissue, as well as
anti-obesity medications, thiazolidinediones, fibrates, angiotensin
receptor blockers, highly active antiretroviral therapy and
hormone replacement therapy. Among visceral adipose tissues,
growing evidences suggest that cardiac adiposity may play
an important role in the development of an unfavorable cardiovascular
risk profile. Recent papers suggest that epicardial fat, index
of cardiac and visceral adiposity, could locally modulate
the morphology and function of the heart. The close anatomical
relationship between epicardial adipose tissue and the adjacent
myocardium should readily allow local paracrine interactions
between these tissues. Echocardiography has been recently
proposed for the direct assessment of epicardial adipose tissue.
Echocardiographic assessment of epicardial fat may be a helpful
tool not only for diagnostic purposes, as marker of visceral
adiposity and inflammation, but also for therapeutic interventions
with drugs that can modulate the adipose tissue. In this article,
epicardial adipose tissue’s structure, function, method
of assessment and reliability as a diagnostic tool and potential
therapeutic target is reviewed.
[Back to top]
Dual Modulation of Vascular Function by Perivascular
Adipose Tissue and Its Potential Correlation with Adiposity/Lipoatrophy
Related Vascular Dysfunction
Y.-J. Gao
Almost every systemic vessel is surrounded by a layer of perivascular
adipose tissue (PVAT), which had been mainly considered as
a mechanical support for vasculature. However, recent advances
have revealed that PVAT is an active player in controlling
vessel function. PVAT releases relaxation factor(s) with unknown
chemical identity (named perivascular adipocyte-derived relaxation
factor, PVRF) that attenuates vasoconstriction to various
agonists including phenylephrine, serotonin, angiotensin II,
and U 46619 (a thromboxane A2
mimic), through activation of K+
channels. PVAT also promotes vasoconstriction to perivascular
nerve stimulation by producing vasoconstrictor or facilitator
(named perivascular adipocyte-derived constricting factor,
PVCF), which includes superoxide and was mediated through
activation of tyrosine kinase and MAPK/ERK pathways. Therefore,
PVAT has a dual regulatory role in modulating vessel function,
attenuating vasoconstriction to agonists by PVRF and promoting
constriction to perivascular nerve excitation by PVCF. In
vivo, normal amount of PVAT (total body fat as well)
is likely to be important in maintaining the homeostasis of
vascular tone and blood pressure, since lipoatrophic mice
developed hypertension. On the other end, excessive accumulation
of body fat (obesity) impaired PVRF production/action, despite
an increase in the amount of PVAT. In spontaneously hypertensive
rats, an animal model of hypertension without obesity, the
ability of PVAT to attenuate vasoconstriction to agonists
was reduced, and treatment with atorvastatin improved PVAT
function. PVAT, vasodilating and constricting factors of PVAT
origin, and signalling pathways of these factors may represent
new targets for developing new strategies to treat vascular
disorders associated with abnormal adiposity.
[Back to top]
Non-Alcoholic Fatty Liver Disease in the Metabolic
Syndrome
G. Palasciano, A. Moschetta, V.O. Palmieri, I. Grattagliano,
G. Iacobellis and P. Portincasa
Non-alcoholic fatty liver disease (NAFLD) is often associated
with features of the metabolic syndrome, carrying an increased
risk to develop non-alcoholic steatohepatitis (NASH), the
inflammatory form of liver steatosis. Epidemiological data
confirm that obesity, diabetes, hypertension and hyperlipidemia
are frequently found in NAFLD and worsen its prognosis because
of increased risk of fibrotic evolution, eventually leading
to liver cirrhosis. Recent studies confirm the close relationship
between the metabolic syndrome and liver steatosis, and further
support the detrimental role of oxidative stress and lipid
peroxidation, which are pathophysiological processes present
in both conditions. Novel diagnostic tools and life style
modifications together with targeted therapeutic actions are
urgently needed for the management of liver dysfunction in
course of metabolic syndrome.
[Back to top]
Targeting the Liver in the Metabolic Syndrome: Evidence
from Animal Models
M. Petruzzelli, G.L. Sasso, P. Portincasa, G. Palasciano
and A. Moschetta
The metabolic syndrome is an emerging global epidemic characterized
by clustering of metabolic abnormalities leading to increased
cardiovascular risk: glucose intolerance or type 2 diabetes,
dyslipidemia, hypertension, and “central” obesity.
Scientists are decoding and piecing together the molecular
texture underlying the metabolic syndrome: insulin resistance
and dyslipidemia stand out as central pathophysiological events.
In this picture, the liver rises as the leading organ in the
maintenance of metabolic fitness; it serves as the first relay
station for processing dietary information, and encloses the
whole biochemical machinery for both glucose and lipid storage
and disposal. In addition, the liver is a target of the different
endocrine molecules secreted by pancreatic β-cells
and adipose tissue. Evidence collected in animal models supports
the central role of the liver in the metabolic syndrome. While
specific bereft of insulin sensitivity in skeletal muscle
and adipose tissue fails to induce diabetes at certain extent,
this is constantly the outcome in case of hepatic insulin
resistance. Also, dyslipidemia is currently interpreted as
the result of increased flux of free fatty acids to the liver
with ensuing misbalance of lipoprotein synthesis and removal.
In this review we bring together recent advances in the field
of lipid sensing nuclear receptors, adipokines and other molecules
responsible for metabolic fitness, and provide a putative
coherent frame to conceive the pathophysiology of the metabolic
syndrome.
[Back to top]
Visceral Fat as Target of Highly Active Antiretroviral
Therapy Associated Metabolic Syndrome
G. Barbaro
HIV-associated lipodystrophy or lipoatrophy, unreported before
the introduction of highly active antiretroviral therapy (HAART),
was first described in 1998, and has a prevalence ranging
from 18% to 83%. As in genetic lipodystrophy syndromes, fat
redistribution may precede the development of metabolic complications
(dyslipidemia, insulin resistance) in HIV-infected patients
receiving HAART. The pathogenesis of HAART-associated lipodystrophy
and metabolic syndrome is complex and a number of factors
are involved, including direct effects of HAART on lipid metabolism,
endothelial and adipocyte cell function, and mitochondria.
Protease inhibitors are responsible for a decrease in cytoplasmic
retinoic-acid protein-1, in low density lipoprotein-receptor-related
protein and in peroxisome proliferator activated receptor
type-gamma. Nucleoside reverse transcriptase inhibitors, and
thymidine analogues, are responsible for mitochondrial dysfunction
as demonstrated by a decrease in subcutaneous adipose tissue
mitochondrial DNA content. Both phenomena are responsible
for a decreased differentiation of adipocytes, increased levels
of free fatty acids and lipoatrophy. The increased levels
of proinflammatory cytokines, such as tumor necrosis factor
(TNF)-alpha and interleukin-6 may further contribute in development
of lipodystrophy. TNF-alfa activates 11-beta-hydroxysteroid
dehydrogenase type-1, which converts inactive cortisone to
active cortisol, resulting in increased lipid accumulation
in adipocytes and insulin resistance. HAART drugs and inflammatory
cytokines are associated with a decrease in adiponectin. The
levels of adiponectin and adiponectin-to-leptin ratio correlate
positively with insulin resistance in HIV-infected patients
with lipodystrophy. HAART-associated metabolic syndrome is
an increasingly recognized clinical entity. The atherogenic
profile of this syndrome may increase the risk of cardiovascular
disease even in young HIV-infected patients. A better understanding
of the molecular mechanisms responsible for this syndrome
will lead to the discovery of new drugs that will reduce the
incidence of lipodystrophy and related metabolic complications
in HIV-infected patients receiving HAART.
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