ADIPOCYTE “FATTY ACID BINDING PROTEIN”
GENE POLYMORPHISMS (rs1054135, rs16909196
AND rs16909187) IN JORDANIANS WITH OBESITY
AND TYPE 2 DIABETES MELLITUS
El-Ryalat S.W.1, Irshaid Y.M.1*, Abujbara M.2, El-Khateeb M.2, Ajlouni K.M.2
*Corresponding Author: Prof. Yacoub M. Irshaid MD, PhD, Department of Pharmacology, College of
Medicine, The University of Jordan, Amman 11942, Jordan. Phone No.: +962 777818284,
Fax No.: +962 6 5300820, Email Addresses: y.irshaid@ju.edu.jo
page: 63
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INTRODUCTION
Obesity is a growing health problem worldwide. An
increase in visceral adiposity is a considerable risk factor
for many metabolic and cardiovascular disorders. Several
studies provide evidence that obesity and weight gain are
associated with an increased risk of developing diabetes
mellitus, high blood pressure, and high cholesterol, while
weight loss decreases this risk [1].
Fatty acid binding proteins (FABPs) are intracellular
lipid chaperones that regulate lipid trafficking and responses
in cells and facilitate lipolysis in adipocytes. At least nine
different isoforms have been identified in mammals [2].
FABP4 (A-FABP) is mainly expressed in adipocytes and
macrophages and have a significant role in the development
of insulin resistance and atherosclerosis. FABP4 plays an
important role as an adipokine, and its increased circulating
levels were associated with metabolic syndrome, obesity,
type 2 diabetes mellitus, insulin resistance, hypertension,
cardiovascular disease, atherosclerosis, cardiovascular
events, alcoholic steatohepatitis, adipose tissue inflamma-tion, diabetic nephropathy, adverse renal outcomes, mortality,
and elevated low-density lipoprotein cholesterol, and
reduced high-density lipoprotein cholesterol [2 - 4].
One prospective study investigated the association
between circulating FABP4 levels and the development
of subclinical atherosclerosis in type 2 diabetes patients
over 8 years. They concluded that FABP4 levels predict
the development of subclinical atherosclerosis in type 2
diabetic patients [5]. Another prospective study over 10
years showed that high FABP4 levels at baseline independently
predicted the development of type 2 diabetes [6].
Both of these studies were performed on Chinese subjects.
FABP4 levels are substantially increased by lipolytic
stimulation. High amounts of circulating fatty acids contribute
to the development of insulin resistance. Long-term
elevation of free fatty acids predispose for inhibition of
insulin-stimulated glucose uptake and glycogen synthesis
and β-cell death [7]. FABP4 deficiency in diet-induced and
genetic obesity mice models resulted in increasing sensitivity
to insulin and reducing hyperinsulinemia. FABP4-
deficient adipocytes have attenuated lipolysis and fatty acid
mobilization both in vitro and in vivo [8]. FABP4 has been
shown to bind to and inhibit insulin receptor signaling [7].
Hundreds of compounds were synthesized in the past
years to serve as FABP4 inhibitors. The purpose was to
find drugs effective in the treatment of atherosclerosis and
diabetes [9]. In preclinical studies using genetic mouse
models, a potent and selective human and murine FABP4
inhibitor (BMS309403) was among them. This inhibitor
has been shown to reduce inflammation and atherosclerosis,
to improve lipid profiles and glucose homeostasis,
and inhibit tumor progression and metastasis [7, 10, 11].
Some studies provided evidence that FABP4 might be a
potential target for some drugs, and inhibitors of FABP4
may serve as therapeutic agents to treat some components
of the metabolic syndrome. Anagliptin, a DPP-4 inhibitor,
was found to reduce FABP4 concentration in patients
with type 2 diabetes and dyslipidemia treated with statins.
The effect was not related to hemoglobin A1c or LDLcholesterol
levels [12]. Metformin was found to inhibit
the intracellular accumulation of lipids in macrophages
and to reduce the expression of FABP4 [13]. A number
of structurally different angiotensin II receptor blockers
given to hypertensive patients reduced circulating FABP4
levels. This effect was not due to blocking their receptors
on adipocytes [13, 14]. Atorvastatin, sitagliptin, and
omega-3 fatty acids were found to decrease circulating
FABP4 concentrations [14].
The aP2 (FABP4) gene locus was mapped to chromosome
8q21. It consists of 4 exons and encodes a 132-amino
acid protein [15]. A functionally significant genetic variation
at the aP2 locus was found to be associated with
decreased adipose tissue expression of the aP2 gene. Subjects
having the T-87C polymorphism had lower serum
triglycerides and reduced risk of coronary heart disease
and type 2 diabetes than individuals with the wild-type
allele [14, 16]. Genomic DNA sequence of the promoter
and coding regions identified 5 distinct SNPs. Two of these
variants (C2600T and G4356C) were previously identified
as rs8192688 and rs1051252, respectively. All of the
SNPs were outside the coding region except the G4356C,
which has been described as a silent variant on exon 4 [16].
Another missense SNP (rs1054135) of FABP4 gene is also
located on chromosome 8 [3]. One study genotyped 7 SNPs
near the FABP4 gene and measured FABP4 levels in older
adults aged 65 years and older [17]. The authors concluded
that there is an association between FABP4 gene SNPs
and fasting glucose levels, but not fasting insulin or body
mass index (BMI). The SNPs rs1054135, rs16909196,
and rs16909187 were among the genotyped SNPs. The
rs16909187 polymorphism was found to have no effect
on FAPB4 concentration in Sorbs from Germany [18].
Few publications are available regarding the association
of FABP4 gene polymorphisms with the development
of type 2 diabetes mellitus and obesity. Such information
is not available among Jordanians. Therefore, we
designed this study to investigate the association of 3 SNPs
in FABP4 gene (rs1054135, rs16909196 and rs16909187)
with type 2 diabetes and obesity in Jordanians.
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