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Uric acid as a modulator of glucose and lipid metabolism

Article  in  Biochimie · June 2015

DOI: 10.1016/j.biochi.2015.06.025 · Source: PubMed

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Contents lists available at ScienceDirect

Biochimie
journal homepage: www.elsevier.com/locate/biochi

Mini-review

Uric acid as a modulator of glucose and lipid metabolism

William Gustavo Lima a, Maria Emília Soares Martins-Santos b,
^nia Chaves a, *

ria Ernesta
Vale
a ~o Joa
Laboratory of Physiology, Federal University of Sa ~o del-Rei, Divino

polis, Minas Gerais, Brazil
b
Metabolic Biochemistry, Federal University of Sa~o Joa
~o del-Rei, Divino
polis, Minas Gerais, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: In humans, uric acid is the final oxidation product of purine catabolism. The serum uric acid level is based
Received 28 January 2015 on the balance between the absorption, production and excretion of purine. Uric acid is similarly pro-
Accepted 26 June 2015 duced in the liver, adipose tissue and muscle and is primarily excreted through the urinary tract. Several
Available online 29 June 2015
factors, including a high-fructose diet and the use of xenobiotics and alcohol, contribute to hyper-
uricaemia. Hyperuricaemia belongs to a cluster of metabolic and haemodynamic abnormalities, called
Keywords:
metabolic syndrome, characterised by abdominal obesity, glucose intolerance, insulin resistance, dysli-
Uric acid
pidaemia and hypertension. Hyperuricaemia reduction in the Pound mouse or fructose-fed rats, as well
Metabolic syndrome
Non-alcoholic fatty liver
as hyperuricaemia induction by uricase inhibition in rodents and studies using cell culture have sug-
Adipose tissue gested that uric acid plays an important role in the development of metabolic syndrome. These studies
Skeletal muscle have shown that high uric acid levels regulate the oxidative stress, inflammation and enzymes associated
with glucose and lipid metabolism, suggesting a mechanism for the impairment of metabolic homeo-
stasis. Humans lacking uricase, the enzyme responsible for uric acid degradation, are susceptible to these
effects. In this review, we summarise the current knowledge of the effects of uric acid on the regulation
of metabolism, primarily focusing on liver, adipose tissue and skeletal muscle.
© 2015 Elsevier B.V. and Socie
te

Française de Biochimie et Biologie Mole

culaire (SFBBM). All rights
reserved.

1. Introduction

Uric acid is a metabolite derived from the oxidation of purine

Abbreviations: ABCG2, ATP-binding cassette transporter 2; ACC, acetyl-CoA
carboxylase; ADH, alcohol dehydrogenase; Akt, protein kinase B; AMP, adenosine
5'-monophosphate; AMPK, AMP activated kinase; ATP, adenosine triphosphate;
ChoRE, carbohydrate response elements; ChREBP, carbohydrate responsive element
binding protein; ERK, extracellular signal-regulated kinase; FAS, fatty acid synthase;
G6P, glucose-6-phosphate; G6Pc, glucose-6-phosphatase; GLUT, glucose trans-
porter; GMP, guanosine 5'-monophosphate; HDL, high density lipoprotein; HOMA-
IR, homeostasis model assessment of insulin resistance; IMP, inosine 5'-mono-
phosphate; IRS, insulin receptor substrate; LDH, lactate dehydrogenase; MAPK,
mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein-1; MRP4,
multi drug resistance protein4; NAD, nicotinamide adenine dinucleotide; NEAC,
nonenzymatic antioxidant capacity; NO, nitric oxide; NPT, Naþ-phosphate
cotransporter; OAT, organic anion transporter; PEPCK, phosphoenolpyruvate car-
boxykinase; PI 3-kinase, phosphatidylinositol 3-kinase; PPAR, peroxisome
proliferator-activated receptor; ROS, reactive oxygen species; SREBP, sterol
responsive element binding protein; SMCT, sodium-dependent monocarboxylic
acid transporters; TAG, triacylglycerol; TORC2, transducer of regulated CREB activity
2; URAT1, urate-anion exchanger.
* Corresponding author. Avenida Sebastia ~o Gonçalves Coelho, 400, Chanadour,
35.501-296, Divino
polis, Minas Gerais, Brazil.
E-mail address: valeria.chaves@gmail.com (V.E. Chaves).
compounds [1]. Since 1981, uric acid has been considered as a
powerful chemical antioxidant, present in human plasma in con-
centrations much higher than ascorbate [2]. It was hypothesized
that uric acid can provide an antioxidant defense in humans against
oxidant- and free radicals-caused ageing and cancer, because uric
acid protects erythrocyte membrane against lipid peroxidation and
lysis induced by t-butylhydroperoxide in concentrations below
those normally found in plasma [2]. Uric acid scavenges free radicals
under hydrophilic conditions, thereby inhibiting lipid peroxidation
on the lipid-aqueous boundary, but this antioxidation is only slight
under lipophilic conditions [3]. In the presence of pre-formed lipid
hydro-peroxides, uric acid might accelerate the copper-induced
peroxidation of human LDL, even in the presence of endogenous
antioxidants [4]. Thus, in hydrophobic environments, uric acid loses
antioxidant ability and becomes a strong pro-oxidant.
More recently, uric acid effect on the development of insulin
resistance, dyslipidaemia and hypertension, important signals of

http://dx.doi.org/10.1016/j.biochi.2015.06.025
0300-9084/© 2015 Elsevier B.V. and Socie
te

Française de Biochimie et Biologie Mole

culaire (SFBBM). All rights reserved.
18 W.G. Lima et al. / Biochimie 116 (2015) 17e23
Table 1
Biochemistry and haemodinamics changes induced by fructose or uric acid.
Fructose
Hyperuricaemia, hypertriglyceridaemia, hypertension
Steatosis
Increase of lipogenesisa
Inhibition of AMPK phosphorylationa
Uric acid
Hypertriglyceridaemia, hypertriglycaemia, hypertension
Increase of lipid contentb
Inhibition of aconitase
Inhibition of Akt and IRS-1 phosphorylation
Stimulation of gluconeogenesis
Inhibition of AMPK phosphorylation
Stimulation of NADPH oxidase
Inhibition of nitric oxide production
Stimulation of renin-angiotensin system
Decrease of adiponectin RNAm
a
Uric acid dependent.
b
Fructokinase independent. [Reference].
metabolic syndrome, has been suggested by clinical and epidemi-
ological studies [5e8] (Table 1).
Purine compounds can be derived from exogenous sources,
such as high protein diets, or endogenous sources, such as the
catabolism of genetic material. The degradation of purine de-
rivatives, such as adenosine 5'-monophosphate (AMP) and gua-
nosine 5'-monophosphate (GMP), generates precursors for the
synthesis of endogenous uric acid [1]. Uric acid synthesis is initi-
ated with the cleavage of phosphate groups from AMP and GMP
through 5’-nucleotidases, releasing adenosine and guanosine
molecules, respectively. Adenosine deaminase converts adenosine
into inosine, while guanosine is converted into free guanine.
Inosine is subsequently hydrolysed to hypoxanthine by purine
nucleoside phosphorylase. Xanthine oxidase catalyses the last two
steps of uric acid synthesis: the conversion of hypoxanthine into
xanthine and uric acid. Guanine is directly converted into
xanthine, which is subsequently converted into uric acid by
xanthine oxidase [1]. AMP deaminase also converts AMP into
inosine 5'-monophosphate (IMP), which is then converted into
inosine by nucleotidases [9,10]. Xanthine oxidase is competitively
inhibited through drugs, such as allopurinol and febuxostat, which
are used in the treatment of pathologies characterised by hyper-
uricaemia [11].
In most mammals, uric acid is subsequently converted into
allantoin by uricase; thus, serum uric acid levels are typically low
[12]. However, between 8 and 12 million years in the Miocene
period, as a result of different point mutations, human ancestors
and other modern primates lost the ability to express the uricase,
and consequently serum uric acid levels have increased [12,13]. It
has been suggested [14] that the loss of uricase in these evolu-
tionary ancestors might have amplified the effects of fructose to
enhance fat stores. These increased lipid reserves could be mobi-
lised in times of energy demand, e.g., during the migration through
large territorial extensions. However, the loss of uricase also in-
creases blood pressure in response to salt [15]. Previous studies
have shown that humans have maintained the set of genes
encoding this enzyme in the liver, however two premature stop
codons do not allow its expression [14,15].
In the absence of uricase, uric acid is the excretion product of
purine metabolism [1]. Uric acid is a weak acid with a high disso-
ciation constant (pKa 5.8). Sodium urate is predominantly (98%)
deprotonated at physiological pH in the bloodstream. Renal (70%)
and biliary (30%) systems are responsible for the removal of urate
from the bloodstream [1,16,17]. Renal excretion depends on the
Model
Rats [20,26]
Rats [21]
Hep G2 [29]
Hep G2 [40]
Model
Humans [6,7], Rats [28]
Hep G2 [29]
Hep G2 [29]
Liver, adipose tissue and muscle of mice, HepG2 [49]
Hep G2 [9]
Hep G2 [9]
Hep G2 [29], 3T3-L1 adipocytes [34]
3T3-L1 adipocytes [34]
3T3-L1 adipocytes [58]
3T3-L1 adipocytes, human subcutaneous adipocytes [27]
dynamic equilibrium between filtration, reabsorption and tubular
secretion. Approximately 90% of the filtrated urate is reabsorbed
through a transport system mediated by urate-anion exchanger
(URAT) 1. This transmembrane protein reabsorbs urate and secretes
anionic organic compounds, such as lactate, ketone bodies and
xenobiotics, through countertransport (Fig. 1). These anionic
organic compounds are released into renal tubular cells through
sodium-dependent monocarboxylic acid transporters (SMCT), such
as SMCT1/2. During secretion, urate enters the cell at the baso-
lateral membrane via exchange with alpha-ketoglutarate, mediated
by OAT1 and OAT3, or through exchange with unknown anions via
OAT2. At the apical membrane, urate is secreted via multi-drug
resistance protein4 (MRP4), adenosine triphosphate (ATP)-bind-
ing cassette transporter 2 (ABCG2), Naþ-phosphate cotransporter
(NPT) 1, and/or NPT4 [1,17].
Serum uric acid levels are controlled through the balance be-
tween urate synthesis and excretion. Several exogenous and
endogenous factors can impair this balance, inducing hyper-
uricaemia [18]. The excessive consumption of fructose, primarily
used in sweetened beverages, has been considered an important
inducer of hyperuricaemia (Fig. 1) [19,20]. Excess fructose increases
fructokinase activity through a positive feedback mechanism via
the activation of carbohydrate responsive element binding protein
(ChREBP) [21]. Fructokinase is responsible for the metabolism of
fructose into fructose-1-phosphate, resulting in adenosine
triphosphate (ATP) depletion in the liver, and this reaction occurs
rapidly and without any negative feedback [22]. The decrease in
intracellular phosphate stimulates AMP deaminase, which cataly-
ses the degradation of AMP to inosine monophosphate, resulting in
a significant increase in serum uric acid levels (Fig. 1) [9,10]. Fruc-
tose and uric acid have been associated with cardiometabolic dis-
eases [21,23], thus the growing consumption of sweetened
beverages in developed and developing countries must be
controlled. Phytocompounds have also been associated with
hyperuricaemia. Methylxanthines, derived from coffee, might be
demethylated and subsequently converted into uric acid through
xanthine oxidase (Fig. 1). Flavonoids stimulate DNA degradation
and inhibit uric acid excretion, thereby elevating serum uric acid
levels (Fig. 1) [24]. In addition, some drugs also inhibit uric acid
excretion. Pyrazinamide, used in the treatment of tuberculosis, and
niacin, used in the treatment of dyslipidaemia, activate URAT1
transporter, thereby stimulating the reabsorption of filtrated urate
(Fig. 1) [1,17]. Alcohol also stimulates this carrier by increasing the
amount of lactate (Fig. 1). In this case, the hepatic metabolism of the
 W.G. Lima et al. / Biochimie 116 (2015) 17e23 19

Fig. 1. Schematic representation of the regulatory factors of synthesis and excretion of uric acid. Fructose and phytocompounds, such as methylxanthines and flavonoids, increase
the rate of the endogenous synthesis of uric acid. Alcohol metabolism increases the levels of NADH, stimulates the lactate dehydrogenase (LDH) and increases the lactate synthesis.
As some xenobiotics, lactate activates the URAT-1 carrier, reducing the excretion of uric acid. An increase in the uric acid synthesis or a decrease in the uric acid excretion can
contribute to hyperuricaemia. ADH, alcohol dehydrogenase; LDH, lactate dehydrogenase; URAT1, urate-anion exchanger.

alcohol dehydrogenase system reduces the coenzyme NADþ to
NADH, which stimulates the conversion of pyruvate to lactate
through lactate dehydrogenase [25]. The lactate anion, generated at
physiological pH, stimulates the activity of URAT1 [1,17].
Normal serum uric acid levels for men and women are 7 and
6 mg dL1, respectively [7,8]. Defects in the balance between uric
acid excretion and synthesis, as described above, induce hyper-
uricaemia (Fig. 1). Epidemiological studies have associated hyper-
uricaemia with metabolic syndrome. The National Health and
Nutrition Examination Survey (NHANES), analysing data from a
cross-sectional study involving 1370 children in the US between
the ages of 12e17 years (1999e2002), has demonstrated a signifi-
cant association between elevated serum uric acid levels and the
increased prevalence of abdominal obesity, hypertriglyceridaemia
and hyperglycaemia [7]. In 2008, a clinical study involving 3518
Caucasian patients between the ages of 21 and 85 years from Albert
Einstein Hospital in Sa~o Paulo showed that serum uric acid levels
were associated with increased triacylglycerol (TAG)/high density
lipoprotein (HDL) and hepatic steatosis, independently of metabolic
syndrome and obesity [6]. In addition, a prospective analysis of the
Framingham heart study involving 4883 patients and a cohort
study involving 4292 patients demonstrated that individuals with
hyperuricaemia developed diabetes mellitus type 2 at significant
higher rate than subjects with normal serum uric acid levels [8]. In
addition, a systemic review and meta-analysis of prospective
cohort studies provided strong evidence that high levels of serum
uric acid are observed independent of other established risk factors,
particularly metabolic syndrome components, for the development
of type 2 diabetes [5]. This clinical evidence indicates that uric acid
might increase the risk for metabolic syndrome, and basic studies
have confirmed these findings (Table 1). Rats administered a 60%
fructose diet for 4 weeks show hyperuricaemia and symptoms of
metabolic syndrome, such as hypertension and hyper-
triglyceridaemia [20,26]. Fructose-fed rats treated with allopurinol,
febuxostat or benzbromarone show normalised plasma uric acid
and insulin levels and decreased TAG levels and systolic blood
pressure [20,26]. The continued administration of fructose induces
a progressive increase in TAG and insulin levels [26]. Recent studies
have demonstrated that lowering uric acid with allopurinol im-
proves the insulin sensitivity and hypertension in Pound mice, two
important features of metabolic syndrome [27]. Chronic hyper-
uricaemia, induced through oxonic acid administration, causes
metabolic alterations, including postprandial hyper-
triglyceridaemia, systemic and glomerular hypertension, and he-
patic TAG accumulation [28]. These findings suggest that uric acid
plays a causal role in the development of metabolic syndrome, and
humans are susceptible to these effects, reflecting a lack of uricase
expression [14]. In this review, we summarise the current knowl-
edge of the effects of uric acid in the regulation of metabolism,
primarily focusing on liver, adipose tissue and muscle.
2. Liver
The evaluation of TAG levels and Oil Red-O staining in the hu-
man hepatocyte cell line HepG2 demonstrated that the lipid con-
tent is significantly increased through uric acid in a dose-
dependent manner (from 0 to 750 mmol L1), while the presence
of the xanthine oxidase inhibitor, allopurinol (100 mM), blocks uric
acid production and TAG accumulation [29]. Previous studies have
shown that lowering uric acid through allopurinol treatment re-
duces hepatic steatosis in several models, such as, ethanol treated-
rats [30], high fat diet-fed Mongolian gerbils [31], fructose-fed rats
[21], and the Pound mouse [29]. The Pound mouse is a model of
prediabetes/metabolic syndrome (Charles River, Wilmington, MA)
20 W.G. Lima et al. / Biochimie 116 (2015) 17e23
manifesting fatty liver, obesity, insulin resistance, and hypertension
in response to a leptin receptor mutation.
In HepG2, uric acid up-regulates fructokinase expression (Fig. 1)
through the activation of the transcription factor ChREBP, leading to
the amplification of the lipogenic effects of fructose [21]. ChREBP is
activated by high glucose, independent of insulin, and this tran-
scription factor is responsible for the transcriptional activation of
lipogenic genes, such as acetyl-CoA carboxylase (ACC) and fatty acid
synthase (FAS), via direct binding to carbohydrate response ele-
ments (ChoRE) in the promoter [32]. Mice lacking fructokinase are
also protected from developing metabolic syndrome when exposed
to a high-fructose diet [33]. However, uric acid also significantly
increases TAG accumulation, even in cells lacking fructokinase and
aldolase B enzyme expression, suggesting that uric acid might
function independently of direct fructose metabolism [29]. Uric
acid increases lipogenesis in HepG2 cells through the inhibition of
mitochondrial aconitase activity and the activation of ATP-citrate
lyase [29]. The inhibition of aconitase activity has been associated
with the significant accumulation of its substrate, citrate, in the
cytosol. Citrate is also a substrate for ATP-citrate lyase, which
converts citrate into acetyl-CoA. The inhibition of ATP-citrate lyase
with radicicol (10 mmol L1) induces an increase in cytoplasmic
citrate levels in response to uric acid and blocks TAG accumulation,
indicating that citrate-stimulated ATP-citrate lyase is involved in
uric acid-mediated TAG accumulation [29]. The inhibition of FAS
activity through Cys75 (10 mmol L1), which ultimately converts
acetyl-CoA and malonyl-CoA into long-chain saturated fatty acids
(palmitate), also prevents TAG accumulation in response to fructose
or uric acid [29]. Thus, uric acid increases fat in hepatocytes
through the stimulation of mitochondrial oxidative stress, which
blocks aconitase and increases citrate, thereby stimulating fat
synthesis [29]. In addition, the silencing of the NADPH oxidase
subunit NOX4 partially prevents the increase in intracellular TAG
levels in response to fructose or uric acid [29]. Fructose also inhibits
mitochondrial aconitase activity and activates ATP-citrate lyase
[29]. Although antioxidant properties of allopurinol suggest that
this drug might have off-target effects, the prevention of fructose-
induced lipogenesis is dependent on the reduction of uric acid
levels, as exogenous uric acid restored the metabolic effects of
fructose [29]. Similar findings were observed in vivo using the
Pound mouse, a metabolic syndrome model that presents hyper-
uricaemia and non-alcoholic fatty liver, leptin receptor defects,
increased visceral fat and insulin resistance. The reduction of uric
acid using allopurinol (30 mg kg1 in drinking water) effectively
reduces hepatic uric acid, TAG and cholesterol content in these
mice. These findings are consistent with a significant decrease in
the activity of the NADPH oxidase subunit NOX4, evaluated by
hydrogen peroxide production, in the mitochondria of Pound mice
treated with allopurinol and with concomitant higher mitochon-
drial aconitase activity and reduced cytoplasmic citrate release
[29]. The effects of allopurinol reducting the activity of NADPH
oxidase in liver mitochondria are consistent with previous data
showing that uric acid in adipocytes stimulates NADPH oxidase
[34].
Studies have shown that uric acid decreases nitric oxide (NO)
production in adipocytes and endothelial cells [34e36]. NO, syn-
thesised via different NO synthase isoforms, elicits changes in O2
consumption, energy-conservation processes and free-radical
production to regulate mitochondrial respiratory functions [37].
The long-term incubation of liver mitochondrial membranes with
NO results in the persistent inhibition of NADH:cytochrome c
reductase activity, observed as inhibited NADH:ubiquinone reduc-
tase (Complex I) activity, whereas succinate:cytochrome c reduc-
tase activity, including Complex II and Complex III electron transfer,
remains unaffected [38]. However, uric acid partially inhibits the
selective effect of NO and derived species [38]. The intraperitoneal
administration of uric acid to ob/ob mice normalises the activity of
complexes I and V in the mitochondrial respiratory chain in he-
patocytes and significantly improves the activity of complexes II
and III [39]. Thus, the reduced nitric oxide levels contribute to the
effects of uric acid on the stimulation of mitochondrial oxidative
stress.
In addition, the generation of uric acid also inhibits AMP-
activated kinase (AMPK) phosphorylation in fructose-exposed
HepG2 cells [40]. AMPK stimulates fat oxidation through the inhi-
bition of ACC1 activity and the transport of malonyl-CoA to the
mitochondria [41] and through the activation of peroxisome
proliferator-activated receptor (PPAR)-a and its downstream target
genes [42]. AMPK also modulates hepatic lipogenesis through
multiple mechanisms, including the inactivation of transcription
factors, such as sterol responsive element binding protein (SREBP)-
1c and -2 [43,44] and ChREBP [45], resulting in the inhibition of the
transcription of lipogenic target genes FAS, ACC1 and stearoyl-CoA
desaturase [43,44]. Thus, the inhibition of the energy sensor pro-
tein AMPK might represent an important step in the development
of non-alcoholic fatty liver [46e48].
Uric acids have also been suggested to play a role in hyper-
glycaemia. Rats with uricase inhibition through oxonic acid
administration show an increased metabolic response to fructose,
with higher glycaemia, blood pressure and renal damage [28].
Hyperuricaemia in mice treated with oxonic acid inhibits protein
kinase B (Akt) phosphorylation (Ser 473) in response to insulin in
the liver, without changes in total Akt content [49]. In vitro hyper-
uricaemia induces oxidative stress in HepG2 cells and inhibits in-
sulin signalling, as demonstrated through the phosphorylation Akt
and insulin receptor substrate (IRS)-1. However, the addition of an
antioxidant blocks this hyperuricaemia-induced insulin signalling
impairment [49]. Thus, the hyperuricaemia effect on liver insulin
resistance is induced through increased oxidative stress. In the
liver, Akt inhibits glycogen breakdown and de novo glucose pro-
duction and stimulates the storage of glucose as glycogen and the
conversion of excess glucose into lipid [50]. Previous studies have
demonstrated that uric acid directly affects hepatic gluconeogen-
esis. De novo glucose production is significantly reduced in HepG2
cells expressing uricases from ancestral hominids compared with
control cells [9]. However, the addition of uric acid activates
gluconeogenesis in a dose-dependent manner, suggesting that the
mechanism whereby uricase blocks glucose production is mediated
through uric acid degradation [9]. Uric acid addition reduces AMPK
activation, induced through the introduction of uricase in HepG2
cells [9]. AMPK activation blocks hepatic gluconeogenesis, in part,
through the inhibition of the transcription rate-limiting enzymes
phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-
phosphatase (G6Pc) [51]. The effects of uric acid on gluconeogen-
esis are mediated through AMPK via the phosphorylation of
transducer of regulated CREB activity 2 (TORC2), as the levels of
TORC2 phosphorylation are increased in uricase-expressing cells
compared with control cells [9]. This phosphorylation inhibits the
transport of TORC2 into the nucleus and the expression of PEPCK
and G6Pc.
These basic biochemistry studies provide evidence that uric acid
might increase the risk for hepatic fat accumulation and hepatic
glucose production, two important signals of metabolic syndrome
[5e8,52].
3. Adipose tissue
Although several studies have demonstrated an increase in uric
acid levels in obese individuals [53,54], it has only recently been
demonstrated that adipose tissue has abundant xanthine
 W.G. Lima et al. / Biochimie 116 (2015) 17e23
oxidoreductase activity, similar to the liver, small intestine and
other organs [55]. Furthermore, mature adipocytes and adipose
tissue produce and secrete uric acid [55]. Thus, it is likely that this
tissue contains all the enzymes necessary for purine catabolism.
Interestingly, the visceral fat area is positively associated with the
serum uric acid levels, indicative of the hyperuricaemia observed in
subjects with type 2 diabetes mellitus [53]. It has previously been
demonstrated that xanthine oxidoreductase is located upstream of
PPARg and regulates the activity of this protein, which regulates
adipogenesis [56]. In addition, obesity increases the mRNA
expression and activity of xanthine oxidoreductase and uric acid
secretion from adipose tissue [55,56]. However, more recently, it
was demonstrated that rats fed a high-fat diet, a model of morbid
obesity, have an increase in xanthine oxidoreductase activity in
subcutaneous, but not in visceral adipose tissue [57].
In adipocytes, uric acid induces oxidative stress, stimulating
NADPH oxidase [34] and the renin-angiotensin system [58]. Soluble
uric acid (15 mg dL1 during 30 min) stimulates an increase in
reactive oxygen species (ROS) production and NADPH oxidase ac-
tivity in mature adipocytes, but not in preadipocytes [34]. It has
recently been demonstrated that renin-angiotensin system in-
hibitors, such as losartan or captopril, prevent the increase in ROS
induced through uric acid [58]. In 3T3-L1 adipocytes, uric acid
(5 mg dL1 for 48 h) increases ROS production and up-regulates the
expression of the proteins involved in the renin-angiotensin system
(angiotensinogen, angiotensin-converting enzyme-1, renin, angio-
tensin type 1 receptor and angiotensin type 2 receptor) and
angiotensin II protein secretion [58]. The stimulation of NADPH
oxidase-dependent ROS through uric acid activates the mitogen-
activated protein (MAP) kinases p38 and extracellular signal-
regulated kinase (ERK)1/2, decreases nitric oxide bioavailability,
and increases protein nitrosylation and lipid oxidation [34].
Oxidative stress in adipose tissue has been recently recognised as a
major causative factor for obesity-related inflammation and
metabolic syndrome [59]. Thus, the oxidative modifications
induced through uric acid contribute to adipose tissue dysfunction.
Indeed, it has been proposed that hyperuricaemia might be
partially responsible for the proinflammatory endocrine imbalance
in the adipose tissue, representing an underlying mechanism of the
low-grade inflammation and insulin resistance observed in sub-
jects with metabolic syndrome [27]. In 3T3-L1 adipocytes, the
presence of uric acid (5 or 15 mg dL1) in incubation medium for 3
days increases the mRNA expression of monocyte chemotactic
protein-1 (MCP-1) and decreases the mRNA expression of adipo-
nectin [27]. These effects are similar in human primary subcu-
taneous adipocytes [27]. Clinical evidence has revealed a negative
correlation between the levels of uric acid and adiponectin in the
serum [60]. A strong positive association between serum leptin and
uric acid has been demonstrated in both diabetic and healthy
subjects [61]; however, this biochemical mechanism still needs
further clarification.
Superoxide scavengers or inhibitors of NADPH oxidase
completely prevent the increase in MCP-1 mRNA induced through
uric acid in adipocytes, suggesting that the urate-induced activa-
tion of MCP-1 expression and secretion in adipocytes is mediated
through superoxide-dependent ROS, likely generated through
NADPH oxidase [27]. Indeed, xanthine oxidoreductase heterozy-
gous knockout mice at 18 months of age show an increase in
oxidative stress levels, characterised by the production of malon-
dialdehyde and H2O2, accompanied by the increased expression of
MCP-1 mRNA in epididymal adipose tissue [62]. However, the effect
of uric acid on adiponectin production is not inhibited in the
presence of superoxide scavengers or inhibitors of NADPH oxidase,
while the addition of rosiglitazone in the incubation medium
restored adiponectin mRNA expression and adiponectin levels to
21
control levels [27]. These experiments suggest that the uric acid-
induced inhibition of adiponectin production is not mediated
through redox-dependent signalling, but rather through a mecha-
nism involving PPAR-g [27]. Similarly, the level of adiponectin
mRNA is decreased in the epididymal adipose tissue of xanthine
oxidoreductase heterozygous knockout mice [62]. It has been pre-
viously suggested that xanthine oxidoreductase is required for the
activation of PPAR-g [Cheung 2007]. However, xanthine oxidase
inhibition with allopurinol in the Pound mice increases adiponectin
mRNA and serum levels and decreases MCP-1 mRNA expression
and serum levels [27]. Additional experiments are needed to clarify
the effect of uric acid, oxidative stress and xanthine oxidoreductase
on the synthesis of inflammatory cytokines in adipose tissue.
However, uric acid might be directly involved in the development
of insulin resistance in adipose tissue. Recently, it has been
demonstrated that hyperuricaemia decreases the phospho-Akt
content in the adipose tissue of mice treated with oxonic acid,
without changes in total Akt [49], thereby inhibiting insulin sig-
nalling. The phosphatidylinositol 3-kinase (PI 3-kinase) and Akt
signalling cascades are major regulators of glucose transporter
(GLUT) 4 exocytosis mediated through small GTPases in adipocytes
[63]. Previous studies have demonstrated that lowering uric acid
also improves insulin sensitivity in Pound mice [27]. Future studies
should evaluate in vivo glucose uptake and lipogenesis in adipose
tissue from hyperuricaemic rodents.
4. Muscle
Elevated serum uric acid is also one of the best independent
predictors of diabetes and typically precedes the development of
both insulin resistance and diabetes [5]. Obese subjects with high
levels of uric acid had lower insulin sensitivity (40%), evidenced by
homeostasis model assessment of insulin resistance (HOMA-IR),
insulin-stimulated glucose disposal, and lower levels of oxidative
stress (30%) markers, compared with obese subjects with normal
uric acid concentration [64]. Previous, it was demonstrated that
decreasing uric acid levels in Pound mice with allopurinol during 8
weeks significantly improves insulin resistance, confirmed through
insulin tolerance tests [27]. Considering that muscle exerts an
important role in glucose homeostasis via insulin, it is possible that
high levels of uric acid could exert some direct effect on this tissue.
Tsushima [55] provided the first evidence that muscle have higher
xanthine oxidoreductase activity in ob/ob than in C57 mice. High-
fat diet also induces an increase in xanthine oxidoreductase activ-
ity in the skeletal muscle from rats [57]. More recently, Zhu [49]
showed that hyperuricaemia induces a decrease in the phospho-
Akt content in the muscle of mice treated with oxonic acid,
without changes in total Akt, thereby inhibiting insulin signalling.
Studies about the role of uric acid in the lipid and glucose meta-
bolism in muscle cells are limited, making the role of this metab-
olite poorly understood in this cell type. Thus, it would be
interesting and necessary to conduct experiments using muscle
cells or tissues in the presence of uric acid to elucidate the direct
connection between high levels of uric acid and insulin resistance
in skeletal muscle.
5. Concluding Remarks
Xanthine oxidoreductase in mammalian organs is predomi-
nantly a nicotinamide adenine dinucleotide (NAD)þ-dependent
dehydrogenase that can be converted into an oxidase either irre-
versibly through limited proteolysis or reversibly through the
chemical or enzymatic oxidation of thiol groups [65e68]. During
oxygen-dependent reactions, this enzyme generates ROS, such as
superoxide anion and hydrogen peroxide [65,69]. Thus, the
22 W.G. Lima et al. / Biochimie 116 (2015) 17e23
reduction of uric acid using allopurinol or febuxostat also decreases
ROS generation, making it difficult to interpret these findings.
However, the administration of the uricosuric agent benzbromar-
one reduces the hyperuricaemia, hypertriglyceridemia, and
hyperinsulinaemia observed in fructose-fed rats [20,70], suggesting
that uric acid is a modulator of glucose and lipid metabolism. In
addition, the hyperuricaemia induced through the administration
of oxonic acid causes metabolic alterations, including postprandial
hypertriglyceridaemia, hypertension, hepatic TAG accumulation
and impairment in response to insulin in liver, adipose tissue and
muscle [28,49]. We believed that in vivo estimative of lipogenesis,
gluconeogenesis, glycolysis and glucose uptake in liver, adipose
tissue and/or muscle are needed to firmly establish the metabolic
effects of uric acid.
Author contributions
All authors contributed to the development, analysis and
drafting of this review article.
Conflicts of interest
The authors have reported no conflicts of interest.
Acknowledgements
The authors would like to thank Renato He
lios Migliorini (in
memoriam) for being an exemplary scientist and professor. This
work was supported through funding from the Federal University
of S~ ~o del-Rei. W.G.L. received a fellowship from the Fundaça
ao Joa ~o
de Amparo a  Pesquisa do estado de Minas Gerais (FAPEMIG).
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