uric acid ( ua ) is the end product of the metabolic pathway for purines , the main constituents of nucleotides .
briefly , inosine monophosphate ( imp ) is derived from de novo purine synthesis and from purine salvage .
hypoxanthine from imp is catalyzed to xanthine and then to uric acid by xanthine oxidase ( xo ) .
de novo nucleotide synthesis generates imp via ribose-5-phosphate , catalyzed to 5-phosphoribosyl-1-pyrophosphate ( prpp ) . in the salvage pathway ,
hypoxanthine - guanine phosphoribosyl transferase ( hgprt ) plays an important role in generating imp , thereby inhibiting ua generation .
since humans are unable to catabolize ua to the more soluble compound allantoin due to lack of urate oxidase or uricase , the serum ua concentration is higher in humans than almost all other mammals .
however , this high ua level in humans has been regarded as being beneficial in the presence of elevated oxidative stress .
ua is oxidized to allantoin and other metabolites via nonenzymatic oxidation   and , thus , ua can function to neutralize prooxidant molecules , such as hydroxyl radicals , hydrogen peroxide , and peroxynitrite .
ua shows the highest scavenging rate constant against o2 , with constants being low against ch3 and t - buoo .
ua directly ( nonenzymatically ) and preferentially deletes nitric oxide ( no ) and forms 6-aminouracil in physiological environments or in association with antioxidants . in vitro ,
ua has both an antioxidant effect on native ldl and a prooxidant effect on mildly oxidized ldl .
it has been suggested that this antioxidant effect of the high ua concentrations in humans contributes to neuroprotection in several neurodegenerative and neuroinflammatory diseases [ 814 ] . however , despite the potential antioxidant effect of ua itself , numerous studies have revealed close associations of serum ua concentrations and various disorders , most of which are included in the metabolic syndrome category .
thus , ua metabolism may be a so - called double - edged sword as regards the inflammatory and/or oxidative responses in many organs , though on the whole , its harmful effects appear to outweigh the benefits of ua in most cases . in this review ,
we first explain the two putative molecular mechanisms underlying inflammation occurrence in relation to ua metabolism ; one is inflammasome activation via ua crystallization and the other involves superoxide free radicals generated by xo . while the ua crystallization mechanism would be dependent on a high serum ua concentration , the latter may not necessarily reflect the serum ua concentration though xo activity does lead to the production of reactive oxygen species ( ros ) .
subsequently , lines of research showing relationships between ua metabolism and the development of various disorders are introduced and discussed .
importantly , recent studies have demonstrated beneficial effects of xo inhibitors against the occurrence and/or progression of several disorders , particularly atherosclerosis and nonalcoholic steatohepatitis ( nash ) , both of which are associated with insulin resistance , hyperlipidemia , and/or obesity . in this review ,
atherosclerosis and nash are discussed extensively , while studies of gout and chronic kidney diseases ( ckd ) are mentioned briefly . in conclusion
, we propose that such xo inhibitors may be more useful for preventing a variety of disorders , such as atherosclerosis and nash , than previously believed , probably via an anti - inflammatory effect .
among the disorders related to hyperuricemia , gout is the most representative and well known .
features of gout include painful arthritis affecting the limbs , caused by reduced ua crystals in the joints . while symptoms of a gout attack are typical of an acute inflammatory response , as indicated by the presence of swelling , heat , rubescence , and pain , there are many disorders with mild but chronic inflammation which are very likely to be related to ua metabolism . in the latter case ,
superoxide free radicals generated by xo are key players leading to chronic inflammatory processes eventually resulting in impaired organ functions .
thus , we introduce two independent mechanisms underlying ua metabolism - induced inflammation . in 2002 ,
the inflammasome concept was proposed to involve multiple proteins and to control the cleavage of prointerleukin 1 ( il-1 ) .
initially , inflammasomes were considered to play a role in immune responses and serve as defense systems against pathogens [ 16 , 17 ] . however
, a line of subsequent studies has elucidated that inflammasomes are key players in the onsets of a wide range of diseases as well as host defense .
excessive metabolites , such as atp or monosodium urate crystals ( muc ) , were also confirmed to be involved in the activation of inflammasomes , and inflammatory responses occurring via inflammasomes have been demonstrated to be linked to the onset and progression of human diseases , including gout , atherosclerosis and nash , as described below in detail [ 1824 ] .
inflammasomes are known to be divided into discernible patterns , depending on component proteins . among them , the nlrp3 inflammasome , comprised of three major components , nod - like receptor 3 ( nlrp3 ) , apoptosis - associated speck - like protein containing a card ( asc ) and caspase-1 , has been well investigated .
first , the toll - like receptor ligands , such as lipopolysaccharide ( lps ) , activate the nf-b pathway and upregulate the expression levels of interleukins , including pro - il-1 and pro - il-18 .
subsequently , the inflammasome complex activated by pathogen - associated molecular patterns ( pamps ) or damage - associated molecular patterns ( damps ) cleaves pro - il-1 or pro - il-18 , resulting in the production of mature interleukins [ 1517 ] .
although the mechanism of inflammasome activation by muc has not been fully elucidated , the following mechanism was proposed .
muc stimulate the toll - like receptor 2/4-myd88 pathway and raise transcriptional levels of pro - il-1 through the nf-b pathway .
it is theorized that muc - induced inflammasome activation is driven by two key factors .
the other is the generation of ros , because an antioxidant , n - acetyl - cysteine , abolished il-1 secretion by muc .
however , the relationship between intracellular k level changes and ros generation remains unknown , and future studies are expected to resolve this issue [ 27 , 28 ] .
elevation of intracellular ros mediates the detachment of thioredoxin - interacting protein ( txnip ) from thioredoxin and enables txnip to associate with nlrp3 , leading to nlrp3 inflammasome activation [ 29 , 30 ] .
thus , muc accumulation promotes inflammatory responses through inflammasomes ( figure 2 ) and thereby promotes the onset of diseases , such as gout .
when mammalian xanthine dehydrogenase ( xdh ) is converted to xo under stressed conditions such as tissue damage and ischemia , superoxide anion and hydrogen peroxide are produced during molybdenum hydroxylase - catalyzed reactions in a molar ratio of about 1  :  3 .
in essence , xo oxidizes a variety of purines and pterins , classified as molybdenum iron - sulfur flavin hydroxylases .
when xo reacts with xanthine , electrons are transferred from mo , fe - s , and fad .
only fadh2 reacts with o2 . in the ua metabolic pathway , xo oxidizes hypoxanthine from nucleic acid metabolites into xanthine and xanthine into ua ( figure 1 ) .
xo , as well as nicotinamide adenine dinucleotide phosphate ( nadph ) oxidase and the mitochondrial electron - transport chain , generates ros .
treatment during pregnancy with allopurinol alters maternal vascular function involving 1-adrenergic stimulation and impairs the fetal 1-adrenergic vasoreflex response involving no .
fetal xo is activated in vivo during hypoxia and xo - derived ros contributes to fetal peripheral vasoconstriction , leading to fetal defense against hypoxia .
xo depletion induces renal interstitial fibrosis , and renal epithelial cells from xor ( / ) mice are more readily transformed into myofibroblasts .
the tissue and cellular distributions of xo in mammals are highest in the liver and intestines due to xo - rich parenchymal cells .
xanthine oxidoreductase ( xor ) is present in hepatocytes , while xo is present in bile duct epithelial cells , concentrated toward the luminal surface .
moreover , in human liver disease , proliferating bile ducts are also strongly positive for xo .
xo activity is low in human serum , the brain , heart , and skeletal muscle , while being rich in microvascular endothelial cells   and is also present in macrophages .
the study using electron spin resonance measurements revealed the contribution of increased xo activity to endothelial dysfunction in patients with coronary artery diseases .
xo activation is induced by lps , angiotensin ii , nadph oxidase , hypoxia , hypoxia - inducible factor 1 , and inflammatory cytokines such as il-1 [ 4649 ] .
the release of xo is increased in hypercholesterolemia , chronic hyperammonemia , thermal trauma , beta - thalassemia , brain ischemia , and pulmonary artery hypertension [ 5054 ] .
indeed , xo was significantly higher in the aortic walls and skeletal muscles of old rats than in those of their young counterparts .
the correlation between plasma xo activity and age is observed in both humans and rats .
it appears that hyperglycemia itself has no impact on liver xo activity , though cardiac , renal , and brain xo activities were shown to be increased in rats with advanced diabetes [ 56 , 57 ] .
xo activity rises remarkably in ischemic congestive heart failure and xo localizes within cd68 positive macrophages .
xo is one of the major superoxide sources in ischemia / reperfusion injuries of the heart , forebrain , skin , liver [ 61 , 62 ] , and gastric mucosa , as well as multiple system organ failure after hind limb reperfusion .
xo activity , along with lipid peroxidation , myeloperoxidase activity and no levels , is increased in the liver in response to renal ischemia / reperfusion in diabetic rats .
ischemia / reperfusion injury is attributable to elevated xo activity and atp depletion related to increasing hypoxanthine and xanthine levels during ischemia , and reperfusion provides o2 for oxidation of these compounds .
superoxide production by xo may also be enhanced by increasing the amount of its substrate , purine bodies .
excess fructose metabolism results in atp depletion which is associated with degradation of amp to hypoxanthine , followed by conversion to ua by xo .
atp depletion , such as that characteristic of glycogen storage disease type 1 , hypoglycemia , exercise , and starvation , also increases ua production . conditions associated with dna turnover , such as tumor progression   and tumor lysis , are also mediated by xo . superoxide produced by xo is an important messenger inducing inflammation and signal transduction , leading to tissue damage .
we found inflammatory cytokines to be induced via xo when foam cells form with lipid accumulation .
xo regulates cyclooxygenase-2   in the inflammatory system , and xo appears to be critical for innate immune function . xo increased egr-1 mrna and protein , as well as the phosphorylation of erk1/2 , while pretreatment with an erk1/2 inhibitor prevented induction of egr-1 by xo .
ros from xo augment trb3 expression in podocytes . as noted above , superoxide from xo
has been suggested to play roles in various forms of inflammatory or ischemic pathophysiology ( figure 3 ) , not necessarily involving hyperuricemia .
while gout is a disorder well known to be caused by the precipitation of ua crystals , the involvement of hyperuricemia in ckd is also widely recognized .
the major causes of ckd have been regarded as diabetes mellitus and hypertension , and thus , hyperuricemia was long viewed as a consequence of ckd . in fact , loss of kidney function reduces the excretion of ua into urine , resulting in hyperuricemia .
in contrast , recent studies demonstrated a significant association between serum ua and the development of ckd . while each metabolic syndrome component , including hyperglycemia , hyperlipidemia , and hypertension , was associated with an increased ckd risk , hyperuricemia was apparently an independent risk factor not influenced by the others .
therefore , hyperuricemia is both a cause and a consequence of ckd and is frequently associated with other metabolic syndrome features . in terms of ckd pathogenesis ,
serum ua is likely to activate the renin - angiotensin system resulting in vascular smooth muscle cell proliferation   and to induce an epithelial - to - mesenchymal transition of renal tubular cells .
xo inhibitor treatment reportedly reduced intercellular adhesion molecule-1 ( icam-1 ) expression in tubular epithelial cells   of mice .
we speculate that ua itself and superoxide free radical generation both play roles in the molecular mechanisms underlying hyperuricemia - related ckd development , but further research is required to elucidate the complex mechanistic interactions between serum ua and ckd . as mentioned in section 2 , both ua and superoxide free radicals are simultaneously produced by xo and might be the pathophysiological cause of these diseases . as shown in figure 3 ,
chronic inflammation is also involved in pathophysiological processes , generally exhibiting a close relationship with oxidative stress .
ros from xo induces lps - induced jnk activation via inactivation of mapk phosphatase- ( mkp- ) 1   and xo regulates cyclooxygenase-2 , one of the master regulators of inflammation . therefore ,
damage from ua , ros , and ua - induced and/or ros - induced inflammation might together contribute to the progression of certain diseases , and distinguishing which mechanism acts first is often difficult in lifestyle - related diseases .
although the relationships between serum ua levels and atherosclerotic diseases , including hypertension [ 85 , 86 ] , have been documented , whether or not serum ua itself is an independent cardiovascular risk factor remains controversial as most hyperuricemic patients with cardiovascular diseases ( cvd ) have other complications such as hypertension , dyslipidemia , diabetes , and ckd as well , which are generally regarded as more established risk factors for cvd than hyperuricemia .
recently , however , a growing body of evidence from both clinical and basic research supports the hypothesis that hyperuricemia , partly via elevated xo activity , is an independent risk factor for hypertension and cvd . despite the association between hyperuricemia and hypertension
having been recognized since the 19th century , it was not until recently that hyperuricemia was demonstrated to be an independent risk factor for hypertension development [ 8793 ] .
a recently published meta - analysis showed that the adjusted relative risk of developing hypertension was 1.48 for hyperuricemic patients , and this association was apparently much stronger in younger , early - onset hypertensive patients [ 86 , 95 ] .
several clinical trials have demonstrated the beneficial effects of ua lowering therapy for hypertension [ 9699 ] . in a trial targeting
prehypertensive obese adolescents , administration of either allopurinol ( xo inhibitor ) or probenecid ( uricosuric agent ) lowered blood pressure .
consistently , both allopurinol and benziodarone ( uricosuric agent ) reduced blood pressure in rats with hypertension induced by hyperuricemia [ 100 , 101 ] , suggesting that not only xo activity but also ua itself plays an important role in the pathogenesis of hypertension . besides the association with hypertension , hyperuricemia or gout has been confirmed to be related to the morbidity and the mortality of cvd [ 102106 ] .
according to a recently published meta - analysis , the relative risks of morbidity and mortality for coronary heart diseases were 1.13 and 1.27 , respectively , in hyperuricemic patients as compared to controls .
several clinical studies have indicated the benefits of xo inhibitors for reducing the incidence of myocardial infarction , improving exercise tolerance in patients with stable angina , and enhancing endothelial function [ 110 , 111 ] .
however , interestingly , unlike the case of treating hypertension , uricosuric agents have failed to show any benefits in patients with hyperuricemia or gout [ 110 , 112 ] .
as described above , xo produces ros when converting hypoxanthine into xanthine and then ua . xo is also expressed in endothelial cells   and was shown to be increased in the aortic endothelial cells of apoe mice , an established model of atherosclerosis .
since oxidative stress inactivates no and leads to endothelial dysfunction , endothelial xo , especially given its enhanced expression during the development of atherosclerosis , contributes to vascular damage via ros production .
recently , we established that xo activity in macrophages also plays a key role in the development of atherosclerosis . during atherosclerosis development , monocytes migrate beneath the endothelium and transform into macrophages , which then turn into foam cells by incorporating modified low density lipoproteins ( ldl ) ( such as oxidized ldl and acetyl ldl ) or very low density lipoproteins ( vldl ) .
foam cells contribute to the formation of unstable plaques by secreting inflammatory mediators and matrix - degrading proteases ( such as matrix metalloproteinases ( mmps ) ) and by generating a prothrombotic necrotic core by eventually undergoing necrotic or apoptotic death .
we demonstrated that allopurinol treatment ameliorated aortic lipid accumulation and calcification of the vessels of apoe - ko mice and that allopurinol markedly suppressed the transformation of j774.1 murine macrophages or primary cultured human macrophages into foam cells in response to stimulation with acetyl ldl or vldl .
the expressions of scavenger receptors ( sr - a1 , sr - b1 , and sr - b2 ) and vldl receptors in j774.1 cells were upregulated by xor overexpression and downregulated by sirna - mediated xor suppression , raising the possibility that xo activity in macrophages positively regulates foam cell formation by increasing the uptake of modified ldl or vldl .
conversely , expressions of abca1 and abcg1 , which regulate cellular cholesterol efflux , were decreased by xor overexpression and increased by xor knockdown .
furthermore , allopurinol suppressed the expressions of inflammatory cytokines such as il-1 , il-6 , il-12 , and tnf , and the expressions of vcam1 , mcp-1 , and mmp2 , which were upregulated in j774.1 cells transformed into foam cells by atherosclerogenic serum .
subsequently , febuxostat , another xo inhibitor , was also demonstrated to attenuate the development of atherosclerotic lesions in apoe mice .
that study showed xo expression to be increased in macrophages infiltrating atherosclerotic plaques and that febuxostat diminished the ros level in the aortic walls of apoe mice .
the authors demonstrated that cholesterol crystals ( ccs ) increased endogenous xo activity and ros production in macrophages and that ccs enhanced not only il-1 release via nlrp3 inflammasome activation but also secretions of other inflammatory cytokines such as il-1 , il-6 , and mcp-1 from macrophages , processes which in turn were suppressed by febuxostat or ros inhibitors .
the significance of nlrp3 inflammasome activation in macrophages by ccs was verified by the observation that atherosclerosis in high - cholesterol diet fed ldl receptor- ( ldlr- ) deficient mice was alleviated by transplanting bone marrow from nlrp3-deficient , asc - deficient , or il-1/-deficient mice .
taking these observations together , we can reasonably speculate that xo in macrophages enhances foam cell formation , ros production , and nlrp3 inflammasome activation , all three of which exacerbate inflammation and plaque formation , thereby contributing to the development of atherosclerotic diseases [ 75 , 114116 ] .
independently of xo , ua itself is widely recognized to exert direct effects on vascular functions .
vascular endothelial cells express several ua transporters   and incorporated ua impairs no production and leads to endothelial dysfunction [ 118 , 119 ] . in vascular smooth muscle cells ,
ua stimulates proliferation and ros production and inhibits no production via increased angiotensin ii expression [ 81 , 120 ] . as noted above , not only xo inhibitors but also uricosuric agents markedly lowered blood pressure , especially in studies targeting early - stage hypertensive patients   and those using animal models [ 100 , 101 ] .
the results obtained suggest that ua presumably contributes to early - stage hypertension by promoting renal vasoconstriction via reduced no production and activation of the renin - angiotensin system [ 86 , 98 ] .
the number of nonalcoholic fatty liver disease ( nafld ) patients including those with nash has been increasing worldwide and a portion of nash patients will progress to hepatocarcinoma onset [ 121123 ] . therefore , numerous investigations have been performed in efforts to elucidate the causes of nash .
nash is characterized by fat deposition , inflammation and fibrosis in the liver , and a two - hit mechanism of onset has been proposed [ 124126 ] .
this hypothesis is that fatty liver formation and subsequent injuries , including inflammation and oxidative stress , cause nash pathology .
interestingly , recent studies have raised the possibility that ua is among the risk factors for nash pathology .
many clinical studies have been carried out to investigate the relationship between serum ua levels and nafld / nash progression .
for example , a cohort study in korea found the serum ua level to be a useful marker for predicting nafld development because the serum ua concentration correlated positively with the 5-year incidence rate of nafld .
their conclusion is supported by another study showing that serum ua levels of nafld patients are higher than those of control groups .
in addition , there are also studies demonstrating that serum ua is a risk factor for the development and/or progression of nafld including nash [ 130132 ] .
consistent with these observations , hepatic xo activities and serum ua levels are reportedly increased in murine nafld / nash models [ 133 , 134 ] . moreover ,
a fraction of nafld / nash patients also have obesity , and hypertrophic adipocytes were also reported to secrete ua . taken together , these results indicate serum ua to be a good parameter for predicting the development of nafld / nash , and that xo inhibitors or uricosuric agents might have potential as treatments for ameliorating the features of nafld . as described above , increasing serum ua or xo activity apparently plays important roles in nafld / nash onset and progression .
fructose treatment of hepg2 cells reportedly increased both the intracellular ua concentration and triglyceride ( tg ) accumulation , while allopurinol , an xo inhibitor , suppressed this fructose - mediated tg deposition .
moreover , the application of ua alone was demonstrated to increase intracellular tg contents as well as ros generation in mitochondria . as a mechanism of
ua - induced tg accumulation , the authors asserted that the elevation of intracellular ros by ua raised both the citrate concentration and atp citrate lyase activity via enhanced phosphorylation at s455 , resulting in the induction of lipogenesis .
these observations are supported by those of another study in which pretreatment with antioxidants inhibited the elevation of triglyceride contents by ua . the authors asserted that ros generation by ua evoked endoplasmic reticulum stress , leading to upregulation of lipogenic genes , such as acetyl coa carboxylase1 and fasn .
ros generation by ua is considered to depend on nadph oxidase activation [ 136 , 138 , 139 ] .
for example , ua reportedly promotes translocation of the nadph oxidase subunit nox4 into mitochondria .
it was also reported that ua treatment raises nadph oxidase activity and alters its localization , leading to lipid oxidation .
in addition , xo may also function as a source of ros generation because xo activity is upregulated in the livers of murine nash models .
collectively , these observations indicate that ua enhances fatty acid synthesis by regulating lipogenesis and induces ros generation by regulating nadph oxidase activity and upregulating fatty acid synthesis , thereby contributing to nash development .
an initial study revealed that inflammasome impairment exacerbated the nash progression induced by feeding a methionine - choline deficient diet for 4 weeks to asc or il-1 ko mice .
for example , it was reported that nlrp3 deficiency prevents liver fibrosis in response to a choline diet deficient in amino acids .
in addition , caspase-1 deficient mice were also resistant to developing steatosis or fibrosis while being fed a high - fat diet .
moreover , other groups have demonstrated that diets which lead to nash also increase the expressions of inflammasome components [ 143145 ] .
taking these lines of evidence together , in the initial stage of nash , inflammasomes appear to exert a protective effect , but continuous inflammasome activation appears to cause excessive productions of inflammatory cytokines , ultimately resulting in liver injury .
although , to date , numerous factors playing important roles in nash progression have been identified , ua also appears to be a key participant in the onset of nafld / nash .
hyperuricemia was reportedly found to be related to insulin resistance in several clinical analyses [ 146152 ] .
in addition , several meta - analyses have suggested the ua level to be positively associated with the development of type 2 diabetes mellitus ( dm ) [ 153156 ] , although mendelian randomization studies did not support circulating ua as being among the causes of dm development [ 157 , 158 ] . in metabolic syndrome patients , an oxidative stress marker , the myeloperoxidase level , was decreased by allopurinol and endothelial function improved . on the other hand , rapid ua reduction achieved by rasburicase , a urate oxidase , in obese subjects with high ua resulted in increasing the markers of systemic and skeletal muscle oxidative stress while having no effect on insulin sensitivity .
furthermore , excess fructose intake is one of the major causes of the development of obesity with hyperuricemia , fatty liver , and metabolic syndrome .
fructose is metabolized by fructokinase to fructose-1-phosphate and results in a drop in both intracellular phosphate and atp levels .
the intracellular phosphate decrease stimulates amp deaminase ( ampd ) , the enzyme catalyzing the degradation of amp to inosine monophosphate and eventually ua . activated ampd increases the expressions of gluconeogenesis genes , that is , pepck and g6pase , via inhibition of amp - activated protein kinase ( ampk ) .
the ua increased fructose - induced tg accumulation and decreased -hydroxybutyrate levels , dose - dependently , while allopurinol , a xo inhibitor , blocked it . because ua is
the downstream product of ampd and allopurinol abolished fructose - induced lipid accumulation , ampd effects on ampk appeared to depend on ua .
ua activates the transcription factor chrebp , which triggers a vicious cycle of fructokinase transcription and accelerated fructose metabolism . via these mechanisms ,
ua is considered to be an antioxidant in human blood , though ua induces oxidative stress in cells .
the stimulation of nadph oxidase - dependent ros by ua resulted in the activation of map kinase p38 and erk1/2 , a decrease in no bioavailability , and increases in both protein nitrosylation and lipid oxidation . increased ua production , in turn , generates mitochondrial oxidants .
mitochondrial oxidative stress inhibits aconitase in the krebs cycle , resulting in citrate accumulation and the stimulation of atp citrate lyase and fatty acid synthase , ultimately leading to de novo lipogenesis . in hepatocytes treated with high ua ,
oxidative stress is increased , which activates serine ( rat ser307 and human ser312 ) phosphorylation of irs-1 .
this activity impairs akt phosphorylation , thereby resulting in acute hepatic insulin resistance after exposure to high ua levels .
therefore , ua - induced lipid accumulation and oxidative stress are responsible for the development of insulin resistance and diabetes .
involvement of increased xo catalyst activity in pathophysiological processes ( figure 4 ) suggests applications of xo inhibitors to the treatment of various disorders . at present , xo inhibitors , including allopurinol , oxypurinol , febuxostat , and topiroxostat , are widely used for treating gout and hyperuricemia .
furthermore , xo inhibitors have been experimentally or clinically shown to exert beneficial effects by lowering serum ua and oxidative stress .
febuxostat preserved renal function in 5/6 nephrectomized rats with and without coexisting hyperuricemia and prevented diabetic renal injury in streptozotocin - treated rats [ 166 , 167 ] .
febuxostat also ameliorated tubular damage , diminished macrophage interstitial infiltration , and suppressed both proinflammatory cytokine activities and oxidative stress .
febuxostat also reduced the induction of endoplasmic reticulum stress , as assessed by grp-78 ( glucose - regulated protein-78 ) , atf4 ( activating transcription factor-4 ) , and chop ( c / ebp homologous protein-10 ) . the clinical significance of measuring the serum ua level and xo inhibition for renal protection has largely been established by the results of recent studies [ 170173 ] . on the other hand , beneficial effects of xo inhibitors on atherosclerosis and nash constitute an evolving concept that has yet to be proven . in rats with fructose - induced metabolic syndrome , febuxostat treatment reversed hyperuricemia , hypertension , dyslipidemia , and insulin resistance
the beneficial effects of xo inhibitors on nash are rarely reported , except by our research group , because animal models of nash with obesity , inflammation , and fibrosis have been difficult to establish .
nash in response to the mcd diet , as used in our studies , caused primarily inflammation and also made the mice lean , such that no benefit of xo inhibition was obtained .
thus , we next used a high - fat diet containing trans - fatty acids and a high - fructose diet to induce nash development in our animal models .
another report showed that inhibition of xo activity also significantly prevents hepatic steatosis induced by a high - fat diet in mice .
tungsten , acting as an xo inhibitor , has an inhibitory effect on both atherosclerosis and oxidative stress .
we reported for the first time that more specific xo inhibition , using allopurinol rather than tungsten on macrophages , resulted in the inhibition of foam cell formation and reduced atherosclerotic lesions in apoe - ko mice , independently of the serum lipid profile .
we also identified phenotypic changes of macrophages in response to allopurinol , such as alterations of gene expressions involved in lipid accumulation .
moreover , both xo overexpression and knockdown of xo expression revealed vldl receptors to be dramatically upregulated by xo .
febuxostat was also proven to have similar effects in terms of reducing the atherosclerotic lesions in apoe - ko mice , and oxidative stress was reduced in macrophages from atherosclerotic lesions .
as a strategy for suppressing atherosclerosis , xo inhibition is expected to act on either macrophages or inflammatory cells .
oxypurinol reduces o2 radical dot production and improves endothelial function in blood vessels from hyperlipidemic experimental animals .
xo inhibition can also provide protection from radiation - induced endothelial dysfunction and cardiovascular complications .
however , controversy persists as to whether the effect of xo on endothelial function is clinically relevant as an interventional target .
pretreatment with xo inhibitors has beneficial effects on ischemia / reperfusion injuries of the intestine , in the impaired liver [ 61 , 62 ] , the edematous brain , kidneys with contrast induced nephropathy , and coronary ischemia .
inflammation related to ua metabolism is induced via either inflammasome activation by ua crystal precipitation or free radical production in response to xo activity .
in addition to gout , many disorders are known to be related to ua metabolism and xo inhibitor treatments have been shown to be effective for preventing the onset and/or the progression of such disorders . in particular , atherosclerosis and nash are diseases for which relationships with ua metabolism were not immediately recognized , but rodent model studies revealed the importance of ua metabolism maintenance for managing these disorders .
we believe the impact of ua metabolism on many diseases accompanying chronic inflammation to have been underestimated .
future studies are anticipated to reveal the pathological contribution of serum ua and/or xo activity to the specific processes underlying various disorders .
 uric acid ( ua ) is the end product of purine metabolism and can reportedly act as an antioxidant . 
 however , recently , numerous clinical and basic research approaches have revealed close associations of hyperuricemia with several disorders , particularly those comprising the metabolic syndrome . in this review , 
 we first outline the two molecular mechanisms underlying inflammation occurrence in relation to ua metabolism ; one is inflammasome activation by ua crystallization and the other involves superoxide free radicals generated by xanthine oxidase ( xo ) . 
 importantly , recent studies have demonstrated the therapeutic or preventive effects of xo inhibitors against atherosclerosis and nonalcoholic steatohepatitis , which were not previously considered to be related , at least not directly , to hyperuricemia . 
 such beneficial effects of xo inhibitors have been reported for other organs including the kidneys and the heart . 
 thus , a major portion of this review focuses on the relationships between ua metabolism and the development of atherosclerosis , nonalcoholic steatohepatitis , and related disorders . although further studies are necessary , xo inhibitors are a potentially novel strategy for reducing the risk of many forms of organ failure characteristic of the metabolic syndrome . 
1. Introduction
2. Inflammation Occurrence Related to UA Metabolism
3. UA Metabolism and Chronic Renal Disease, Atherosclerosis, Heart Failure, and NASH
4. Beneficial Effects of XO Inhibitors
5. Conclusion