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American Journal of Physiology - Regulatory, Integrative and Comparative Physiology logoLink to American Journal of Physiology - Regulatory, Integrative and Comparative Physiology
. 2022 Mar 10;322(5):R347–R359. doi: 10.1152/ajpregu.00238.2021

Sirtuin deficiency and the adverse effects of fructose and uric acid synthesis

Bernardo Rodriguez-Iturbe 1,2,, Richard J Johnson 3,4, Miguel A Lanaspa 5, Takahiko Nakagawa 6, Fernando E Garcia-Arroyo 2, Laura G Sánchez-Lozada 2,
PMCID: PMC8993531  PMID: 35271385

Abstract

Fructose metabolism and hyperuricemia have been shown to drive insulin resistance, metabolic syndrome, hepatic steatosis, hypertension, inflammation, and innate immune reactivity in experimental studies. We suggest that these adverse effects are at least in part the result of suppressed activity of sirtuins, particularly Sirtuin1. Deficiency of sirtuin deacetylations is a consequence of reduced bioavailability of its cofactor nicotinamide adenine dinucleotide (NAD+). Uric acid-induced inflammation and oxidative stress consume NAD+ and activation of the polyol pathway of fructose and uric acid synthesis also reduces the NAD+-to-NADH ratio. Variability in the compensatory regeneration of NAD+ could result in variable recovery of sirtuin activity that may explain the inconsistent benefits of treatments directed to reduce uric acid in clinical trials. Here, we review the pathogenesis of the metabolic dysregulation driven by hyperuricemia and their potential relationship with sirtuin deficiency. In addition, we discuss therapeutic options directed to increase NAD+ and sirtuins activity that may improve the adverse effects resulting from fructose and uric acid synthesis.

Keywords: fructose, metabolic syndrome, NAD+, sirtuins, uric acid

INTRODUCTION

Fructose is a unique nutrient that triggers a biological pathway that drives hunger, foraging behavior, reduced resting energy metabolism, stimulation of fat and glycogen storage, insulin resistance, salt retention and rise in blood pressure, low-grade inflammation, and a relative reduction in mitochondrial energy production (1). These effects may result from the ingestion of foods rich in fructose, but fructose can also be generated endogenously by the polyol-fructose-uric acid (PFU) pathway in response to high-glucose or high-salt diets or in response to stress (24). Although intended as a survival system, overactivity of this pathway in humans could be playing a contributory role in the epidemics of obesity, diabetes, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and chronic kidney disease (CKD).

The biological mechanisms activated by the PFU pathway are initiated by the rapid reduction in ATP that occurs when fructose is phosphorylated to fructose-1-phosphate by the enzyme fructokinase (ketohexokinase) C. This enzymatic reaction is associated with a fall in intracellular phosphate that triggers activation of AMP deaminase that removes AMP substrate while stimulating adenine nucleotide degradation to generate uric acid. Uric acid enters the mitochondria where it induces oxidative stress that reduces ATP production by both the Krebs cycle and β-fatty acid oxidation (5). These processes maintain low intracellular ATP levels, which in turn act as an alarm signal that triggers metabolic homeostatic responses (6).

Since uric acid has a central role in driving the biological effects of the PFU pathway, it is not surprising that elevations in serum uric acid have been found to be associated with the injurious clinical conditions resulting from fructose and uric acid synthesis. However, there remains debate on whether reducing uric acid synthesis in clinical studies can help prevent or improve hypertension, diabetes, and kidney disease. Reviews of the evidence have concluded that reduction of serum uric acid improves, (7, 8) or does not modify (911) renal and cardiovascular outcomes. The two most recent clinical trials (12, 13) did not demonstrate significant benefits of reducing uric acid on the progression of kidney disease. In a comprehensive review, Mauer and Doria (14) suggested that the discrepancies may be attributable to other metabolic traits. However, these latter two studies excluded subjects with gout (who are predicted to be the best responders) while including subjects with normouricemia (who would be predicted to not respond) (15).

Here we argue that another potential reason for the absence of demonstrable benefit is that the adverse effects of hyperuricemia are due to sirtuin deficiency that results from reduction of its cofactor nicotinamide adenine dinucleotide (NAD+). Reduction of NAD+ is an expected consequence of activation of the PFU pathway and of uric acid-driven inflammation and oxidative stress. For example, Sirtuin 1 (SIRT1) expression is reduced in hyperuricemia induced by yeast polysaccharide plus potassium oxonate (16), and we observed a 50% reduction in SIRT1 expression in Wistar rats in which uric acid was raised twofold by uricase inhibition (unpublished observations). We have also reported that endogenous fructose metabolism that occurs in type 1 diabetes drives a decrease in NAD+ in the kidney in association with the development of kidney disease (17). If hyperuricemia cause its deleterious effects by lowering NAD+, then the degree of compensatory regeneration of NAD+ and its effects on the NAD+-to-NADH (NAD+/NADH) ratio might influence the metabolic manifestations associated with hyperuricemia as well as the degree of benefit associated with lowering uric acid levels. A correlate to this would be that treatments directed to increase NAD+ and SIRT1 abundance might provide additional benefit in the treatment of metabolic dysfunction induced by hyperuricemia.

Given this hypothesis, we review how fructose and uric acid metabolism could lead to sirtuin deficiency, and how the sirtuin deficiency might be able to account, at least in part, for the adverse effects associated with hyperuricemia and fructose metabolism.

URIC ACID, NAD+ DEPLETION, AND SIRTUIN DEFICIENCY

Sirtuins are protein deacetylases that require NAD+ as a cofactor for their enzymatic activity. They derive their name from the silent information regulator 2 (SIR2) gene that two decades ago was shown to extend the replicative life span of yeast (18). The seven members of the sirtuin family (SIRT1-7) are localized in the cytoplasm and nucleus (SIRT1, SIRT2), nucleus (SIRT6), mitochondria (SIRT3, SIRT4, and SIRT5), and in the nucleolus (SIRT7) (19). SIRT1 is the best studied. In their deacetylase function, sirtuins interact with NAD+-generating nicotinamide (NAM) that is a negative regulator of sirtuins’ activity. NAD+ and its reduced form NADH are both sensors and participants in the cellular redox state. In normal conditions the ratio of NAD+/NADH that keeps sirtuins constitutively active is 800/1 in the cytosol and nucleus and 7/1 in the mitochondria. It is the level of NAD+ that determines the function of sirtuins since SIRT1 has 1,000 times higher affinity for NAD+ than for NADH (20).

NAD+ regeneration depends on the de novo synthesis and the salvage pathway. De novo NAD+ synthesis is driven by the kynurenine pathway of tryptophan degradation and the Preiss-Handler pathway. The salvage pathway reconstitutes NAD+ from nicotinamide adenine mononucleotide (NAM), nicotinamide riboside (NR), and nicotinic acid precursors originated in NAD+ consumption (21). In mammalian cells, regeneration of NAD+ occurs predominantly by the salvage pathway (22).

There are several ways NAD+ depletion could occur via the fructose-uric acid metabolism (Fig. 1). First, the production of fructose from sorbitol requires NAD+, so stimulation of the polyol pathway, such as by ingestion of high glycemic foods, sugar or salty foods, starts with NAD+ consumption (3, 4). Second, during fructose metabolism there is the generation of uric acid from adenine nucleotide breakdown products. One mechanism is by the degradation of hypoxanthine and xanthine to uric acid via the enzyme xanthine dehydrogenase (XDH), which also consumes NAD+ (23). Uric acid can also be generated by xanthine oxidoreductase (XOR) with the production of oxidants; when NAD+ levels become low, XDH will produce oxidants instead of consuming NAD+ (23). Once the uric acid is generated, it stimulates production of fructose (increasing aldose reductase activity) as well as the metabolism of fructose (increasing fructokinase activity) in a positive feedback loop (24, 25) that amplifies the NAD+ depletion (Fig. 1).

Figure 1.

Figure 1.

Polyol-fructose-uric acid (PFU) pathway activation reduces the intracellular NAD+/NADH ratio. Diets high in sugar, fat, and salt activate the polyol pathway decreasing NAD+ through sorbitol dehydrogenase activity to synthesize endogenous fructose. Increased metabolism of fructose by fructokinase C (KHK-C) transiently depletes ATP due to phosphorylation to fructose-1 phosphate (F-1P). Sequestration of phosphorous in F-1P activates the purine degradation pathway by activating adenosine monophosphate deaminase 2 (AMPD2), Uric acid is generated from xanthine and/or hypoxanthine by xanthine dehydrogenase (which reduces NAD+ levels) or by xanthine oxidoreductase (XOR) activity (which generates superoxide anion and hydrogen peroxide). In turn the uric acid blocks AMP-activated protein kinase (AMPK) and stimulates mitochondrial oxidative stress by stimulating NADPH oxidase 4 (NOX4) in the mitochondria (especially affecting mitochondrial complex 1). The oxidative stress reduces aconitase, thereby blocking ATP production through the Krebs cycle, but also block fatty acid oxidase via effects on enoyl CoA hydratase and via effects on AMPK. These mitochondrial effects reduce the NAD+/NADH ratio. Furthermore, oxidative stress induces vascular damage by reducing nitric oxide (NO) availability causing endothelial dysfunction and promoting hypertrophy of vascular smooth muscle cells (VSMC). Such vascular effects induce vasoconstriction, ischemia, and hypoxia, which also reduces the NAD+/NADH ratio and stimulates glycolysis. Inside dashed lines are additional probable mechanisms (not yet proven) by which PFU activation might reduce the NAD+/NADH ratio. The formation of advanced glycation products by fructose can increase oxidative-nitrosative stress, activating Poly (ADP) ribose polymerase 1 (PARP-1). In blue, control points where SIRT1-activating compounds have been shown to be beneficial and could potentially reduce deleterious effects of PFU pathway activation (see text).

Uric acid can also be directly involved in depleting NAD+. For example, consumption of NAD+ occurs in sirtuin-induced deacetylation and is also a feature of the activation CD38 (NAD cADP ribose hydrolase) and of the activation of poly ADP-ribose polymerase (PARP) enzymes, especially PARP-1, in response to oxidative stress and DNA injury (26). Uric acid drives consumption of NAD+ by activating CD38 with uric acid crystals (27) and by activating PARP-1 as a consequence of intracellular uric acid generation of oxidative stress (5, 28, 29).

The multiple steps by which the PFU pathway and uric acid can lower NAD+/NADH ratio are shown in Fig. 1. We include specific control points in which SIRT1 activating compounds have been shown to have beneficial effects (3032).

SIRTUIN DEFICIENCY, FRUCTOSE METABOLISM, AND URIC ACID SYNTHESIS HAVE SIMILAR METABOLIC EFFECTS

The function of sirtuins is central in metabolic homeostasis. Table 1 shows specific deacetylase reactivities that, if absent, could drive the metabolic dysregulation that fructose and uric acid synthesis could cause via NAD+ consumption.

Table 1.

Deacetylated targets of sirtuins relevant to the polyol-fructose-uric acid pathway

Deacetylation Target (Refs.) Sirtuins How Sirtuins Acts Result
PTP1B (33) SIRT1 Inactivates PTP1B (negative regulator of insulin receptor) Increases insulin signaling and prevents leptin resistance
FoXO1 (34, 35, 36) SIRT1, SIRT2,SIRT6 Translocates FoXO1 to nucleus with transcription of target genes Improves insulin signaling, suppresses lipogenesis, and increases lipolysis
FoXO3a (37) SIRT2 Activates antioxidant response Suppresses oxidative stress
P3K/AKT pathway (38) SIRT1 Translocation of Akt to cell membrane and activation Improves cell signaling and metabolism
Complex I and II (39) SIRT1-SIRT3 Activation of electron transfer chain Improves insulin sensitivity and reduces oxidative stress
CRCT2 (40, 41) SIRT1 Ubiquitination of deacetylated CRCT2 Suppresses lipogenesis
SREBP-1 (42) SIRT1 Inhibits transactivation Suppresses lipogenesis
PPARγ (43) SIRT1, SIRT2 Reduced PPARγ activity Increases lipid oxidation
PGC-1α (44, 45) SIRT1, SIRT2, Activates transcriptional activity and modulates mitochondrial biogenesis Stimulates autophagy and reduces oxidative stress
Stearoyl-CoA desaturaselong chain acy-CoA dehydrogenase (46) SIRT3 Inactivation Reduces lipogenesis
LXR (47) SIRT1 Upregulation Reduces lipogenesis
NRF2 (48, 49) SIRT1, SIRT2 Transactivation of target antioxidant genes (MnSOD, catalase, heme oxygenase) Reduces oxidative stress
NF-κB RelA/p65 (50, 51,52) SIRT1, SIRT3 Inactivation and ubiquitination of NF-κB Anti-inflammatory effect and suppression of NLRP3 inflammasome activation
AP1 (53) SIRT1 Suppresses AP1 transcriptional activity and reduces COX2 and PGE production in macrophages Anti-inflammatory effect
LKB1 (42, 41) SIRT1 Activates AMPK Increases lipid oxidation
HIF-1α (54, 55) SIRT1, SIRT6 Suppresses glycolytic enzymes Switch from aerobic glycolysis to lipid oxidation
AMPK (31) Activation of AMPK and PGC1-α Improves mitochondrial function and metabolism
P53 (56) SIRT6 Repression of p53activity and inhibition of Fas/FaL signaling Reduces apoptosis and reduces oxidative stress
STAT3 (57) SIRT1 Suppression of IL-6/ STAT pathway Reduces inflammation
HSP90 (58) SIRT2 Disassociation of HSP90 with glucocorticoid receptor Reduces inflammatory cytokines

Sirtuin targets for deacetylation and how they improve features of metabolic syndrome and inflammation are shown. AkT, protein kinase B; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; AP1, activator protein 1; CRTC2, CREBP-regulated transcription co-activator 2; HIF1-α, hypoxia inducible factor 1-α; FoxO, forkhead transcription factor O; HSP90, heat shock protein 90; LKB1, liver kinase B1; LXR, liver X receptor; NRF2, nuclear factor E2-related factor 2; PGC1-α, peroxisome proliferator-activated receptor γ coactivator 1-α; PPARγ, peroxisome proliferator-activated receptor-γ; PTP1B, protein tyrosine phosphatase 1B; SREBP-1, sterol regulatory element binding protein 1; STAT3, activator of transcription 3.

Insulin Resistance

Insulin resistance has been shown to result from activation of the PFU pathway. Hyperuricemia is associated with inhibition of endothelial nitric oxide (NO) synthase and increase NO scavenging which blocks the insulin-induced increase in blood flow to skeletal muscle (28, 59). Uric acid may also cause insulin resistance by affecting mitochondrial function and inhibition of AMP-activated protein kinase (AMPK) (60) that results in increased gluconeogenesis (61). In addition, the PFU pathway stimulates the synthesis of vasopressin (62) that binds to the V1b receptor to stimulate glucagon and ACTH, both of which also have a role in driving the insulin resistant state.

Insulin resistance and diabetes are among the best recognized features of deficiency of SIRT1 and, to a lesser extent, deficiency of SIRT2. SIRT3, SIRT5, and SIRT6 (29, 6366). The mechanisms that cause diabetes include both impairment in insulin signaling pathways and dysfunctional pancreatic insulin secretion.

SIRT1 promotes insulin-signaling (Table 1). Deacetylation maintains phosphorylated substrates that drive the activation of the phosphoinositide 3 kinase-protein kinase B (PI3K-Akt) pathway that is central to insulin sensitivity in muscle cells (66). Deacetylation of Akt is essential for Akt membrane localization and activation. In addition, SIRT1 suppresses the transcription of protein tyrosine phosphatase (1B PTP1B), which is a negative regulator of insulin transcription, by deacetylating the histone in its promoter (66) SIRT1 deacetylation of forkhead transcription factor O1 (FoxO1) sustains phosphorylation of insulin receptor substrate 2 (IRS2) and promotes gluconeogenesis-related genes (34). The beneficial effects of SIRT1 agonists on insulin sensitivity have been confirmed in the SIRT knockout (KO) mice (38, 67, 68).

Deficiency of other sirtuins also induce insulin resistance. SIRT2 deletion impairs deacetylation and activation of FoXO1 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), which are direct Akt targets (69). SIRT3 also deacetylates and activates Complex I and Complex III of the electron transport chain. In fact, the beneficial effects of SIRT1 on insulin sensitivity are linked to SIRT3 stimulation of Complex I (39). Inhibition of Complex I reduces the NAD+/NADH ratio and, thereby, causes deficient SIRT3 activity. Insulin resistance resulting from global deletion of SIRT3 is associated with reduction of glucose oxidation due to hyperacetylation and reduction of the activity of pyruvate dehydrogenase.

The roles of other sirtuins in insulin sensitivity are less defined: SIRT6 deficiency reduces insulin sensitivity in the muscle, whereas transgenic SIRT6 expression has the opposite effect. SIRT7 inhibits glycolysis in liver cell cultures.

In addition to giving support to the insulin signaling cascade, sirtuins also modulate pancreatic insulin secretion. SIRT1 transgenic mice have increased secretion of insulin in response to low glucose. The increased β cell response is the result of the binding of SIRT1 to the promoter of uncoupling protein 2 (UCP2), thereby suppressing UCP restrain of ATP generation and promoting glucose-induced Ca+ influx in β cells (70). In addition, SIRT1 protects β cells against oxidative stress by deacetylating and activating FoxO1. SIRT3 also protects β cells and insulin secretion since SIRT3 KO increases apoptosis and death of β cells (63) and SIRT6 deletion in β cells reduces the insulin response to hyperglycemia. In contrast with other sirtuins, SIRT4, a rogue sirtuin with varying enzymatic and substrate activities depending on the tissue, inhibits insulin secretion by suppressing the generation of ATP in β cells by repressing the activity of glutamate dehydrogenase (20).

Therefore, deficient activity of sirtuins resulting from NAD+ depletion could play a major role in the insulin resistance associated with fructose and uric acid metabolism.

Increased Fatty Acid Synthesis, Reduced Fatty Acid Oxidation, and Hepatic Steatosis

The PFU pathway and the uric acid generated have also been found to stimulate both carbohydrate-responsive element-binding protein (ChREBP) and sterol regulatory element binding protein 1 (SREBP-1)-mediated pathways (71). Uric acid-induced lipogenesis occurs as a consequence of mitochondrial oxidative stress that causes a reduction in aconitase activity with citrate accumulation, activation of ATP citrate lyase and fat synthesis (5). The oxidative stress also degrades enoyl CoA hydratase involved in fatty acid oxidation, thereby reducing ATP generation and stimulating fatty acids synthesis (5). In addition, fructose-induced insulin resistance results in high insulin levels that may further stimulate fat accumulation by reducing lipolysis in adipocytes (72, 73). The stimulation of vasopressin synthesis (discussed earlier) by fructose also upregulates fructokinase levels and the metabolism of fructose (74).

Lipogenesis and nonalcoholic fatty liver disease (NAFLD) are well-recognized consequences of sirtuin depletion (40). The histologic hallmark of NAFLD is the deposition of triglycerides in the form of lipid droplets in hepatocytes. Sirtuin deficiency drives NAFLD by enhancing lipogenesis, reducing fatty acid oxidation, and impairing lipid removal (Table 1). Liver tissues from subjects with NAFLD have reduced levels of SIRT1, SIRT3, SIRT5, and SIRT6 (and upregulation of SIRT4) (75). Plasma SIRT1 levels are also low in obese patients with NAFLD (76).

Genetic SIRT1 deficiency promotes and SIRT1 activators protect against fatty liver disease (41, 77, 78). Relevant to our postulates that SIRT1 deficiency plays a role in the development of hepatic steatosis associated with the activation of the PFU pathway, fructose-induced NAFLD has shown to be mediated by NAD+ and sirtuin depletion (36, 79).

Other sirtuins that reduce fat accumulation are SIRT2, SIRT3, and SIRT6 (Table 1). SIRT2 mRNA is abundant in adipose cells and SIRT2 deaceylates FoXO1, represses peroxisome proliferator-activated receptor-γ (PPARγ) and suppresses adipogenesis (35). SIRT3 deletion induces metabolic syndrome and accelerated western diet-induced obesity (46). SIRT6 deletion accelerates diet-induced obesity and transgenic SIRT6 overexpression increases resistance to obesity (80, 81). Not surprisingly, SIRT4 shows contrary effects: it inhibits fatty acid oxidation and SIRT4 KO mice shows protection against diet-induced obesity.

The role of sirtuin deficiency in NAFLD is supported by recent studies using SIRT1 microRNA inhibitors. miRNA-122 is a biomarker of NAFLD (82) and knockdown inhibition of miR-122 increases SIRT1 and protects hepatocytes from diet-induced NAFLD (83). In mice with NAFLD, there is upregulation of miRNA-421 and suppression of miRNA-421 increased SIRT3 and improved NAFLD (84). Of interest, in mice fed a high-fat diet, hyperuricemia is associated with high levels of miRNA 149-5p and hepatocyte lipid accumulation (84). Circulating miRNAs have been investigated in patients with hyperuricemia and gout (85), but, to our knowledge, the association between mRNAs with sirtuins activity has not been examined in humans.

Central leptin resistance is also an important mechanism by which fructose metabolism promotes obesity (4). Both central and peripheral leptin resistance are features of deficiency of SIRT1 that can be improved by resveratrol (86). SIRT1 activity downregulates protein tyrosine phosphatase 1B (PTP1β) that induces leptin resistance (87) and, therefore, leptin resistance that occurs in fructose metabolism could represent another consequence of SIRT1 deficiency.

Mitochondrial Oxidative Stress

Uric acid has been shown to cause mitochondrial oxidative stress by translocating NADPH oxidase to the mitochondria (5). There is also evidence that uric acid itself accumulates in the mitochondria (88) where it may reduce antioxidant pathways, thereby increasing oxidative stress (89, 90).

SIRT1 deficiency may be mediating the oxidative stress induced by uric acid. SIRT1 is a well-known regulator of mitochondrial homeostasis and oxidative stress (91). As shown in Table 1, SIRT1 protects from oxidative stress by several mechanisms. First, SIRT1 deacetylates PGC-1α (44) that activates mitochondrial gene transcription. SIRT1 also deacetylates and activates autophagy regulators ATG5, ATG7, and ATG8 (92). Furthermore, SIRT1 deacetylates FoxO1 and FoxO3 promoting the expression of autophagy components (93) and deacetylates and activates nuclear factor E2-related factor 2 (NRF2) and its target antioxidant genes, inducing overexpression of MnSOD, catalase, and heme oxygenase-1 (48). Sirtuin depletion and inflammation-induced nitrosylation of SIRT1 abrogate sirtuin’s protective antioxidant effects (94, 95).

Other sirtuins are also important in the antioxidant response. SIRT 2 deacetylates PGC-1α, FoXO3a (transcriptional activator of SOD gene), and NFR2 (49) and also ameliorates oxidative stress and epigenetic DNA damage. SIRT3 is a mitochondrial sirtuin that, as mentioned earlier, deacetylates energy complexes of the electron transport chain (96, 97) and mediates the beneficial antioxidant effects resulting from caloric restriction in diabetes and obesity (66). SIRT5 also plays a role in the antioxidant response but its activity is mostly mediated by desuccinylation, not deacetylation. SIRT6 and SIRT7 also participate in the antioxidant response but their role is incompletely defined (30).

In general, all sirtuins except SIRT4 play an important role in buffering reactive oxygen species, a function made evident by the increase in oxidative stress resulting from their deletion. Thus, the reduction in the activity of sirtuins likely plays an important role in the oxidative stress resulting from increased intracellular uric acid.

Inflammation and Innate Immunity

Uric acid crystals activate inflammasomes with the production of interleukin-1 (IL-1) and other inflammatory cytokines that drive inflammation in gout (98). Uric acid crystals also cause NAD+ consumption via stimulation of CD38 (27). Recently, urate crystals have been reported to deposit in the blood vessels and kidneys of gouty subjects where they likely stimulate local and systemic inflammation (99). Studies using special imaging (dual energy CT scans) suggest this may be much more common than presumed, and that nearly 80% of patients with gout may have some crystals in their coronary arteries and aorta (100). Even in asymptomatic hyperuricemia, up to 30% of the cases present clinically silent urate crystals deposits (101). Although original studies suggested that it was the crystalline uric acid that drives inflammation, there is evidence that soluble uric acid can activate inflammatory pathways, including p38 MAP kinase, NF-κB, and inflammasome-based pathways (58) and there is also evidence that uric acid can stimulate inflammatory chemokines and cytokines from resident cells, an effect that is inhibited by the blockade of urate anion transporter 1 with probenecid (102). Furthermore, asymptomatic hyperuricemia activates the innate immune system (103).

In contrast, sirtuins have anti-inflammatory properties and reduction in sirtuin activity stimulates inflammation (104) (Table 1). SIRT1 inhibits NF-κB activity by deacetylation of the lysine 310 of RelA/p65 (50) that impairs recruitment of a coactivator (bromodomain-containing protein Brd4) and increases NF-κB ubiquitinaton (51, 52). SIRT1-induced deacetylation also reduces the activation of proinflammatory NF-κB-dependent genes by inactivating its cofactor p300/CBP (p300/CREB binding protein) and also deacetylates activator protein 1, inhibiting the expression of the proinflammatory phenotype of macrophages (53). Furthermore, SIRT1 stimulates immune tolerance by decreasing the IL-17-to-Treg ratio (105, 106). Conversely, deletion of SIRT1 increases the activation of the NLRP3 inflammasome (107) and the SIRT1 KO mice present generalized T-cell activation and breakdown of CD4 tolerance with generation of autoantibodies (108).

Other sirtuins also induce anti-inflammatory responses but have been less extensively investigated. SIRT2 deacetylates the p65 subunit of NF-κB at lysine 310 and also reduces inflammation interacting with heat shock protein 90 (HSP90) (33). SIRT3 inhibits NF-κB and inactivates the NLRP3 inflammasome (109). SIRT6-induced deacetylation suppresses the activation of the promoter region of p65 and deletion of SIRT6 upregulates proinflammatory genes. SIRT7 deletion results in myocardial immune cell infiltration (110). Therefore, the proinflammatory effects of hyperuricemia could potentially be mediated by sirtuin deficiency driven by NAD+ reduction.

Aerobic Glycolysis

Inflammation is associated with a switch from lipid oxidation to the less efficient but faster energy generation of aerobic glycolysis. Fructose has also been shown to drive aerobic glycolysis (111), which may in part be from mitochondrial oxidative stress that dampens mitochondrial energy production. Nakagawa et al. (112) recently reviewed the mechanisms by which fructose activates aerobic glycolysis. Briefly, uric acid blocks aconitase, a key enzyme in the tricarboxylic acid cycle in the mitochondria and the increased energy demands drive the switch to activate aerobic glycolysis, described initially for cancer cells (Warburg effect). Increased lactate production is a primary gluconeogenic substrate that further feeds glycolysis (113).

The bioavailability of NAD+ and activity of sirtuins are linked to the changes in aerobic glycolysis and fatty acid oxidation that result from acute and chronic inflammation (55). As discussed earlier, SIRT1 deficiency has been shown to stimulate aerobic glycolysis and suppress fatty acid oxidation. In addition, SIRT1 and SIRT6 coordinate the change to fatty acid oxidation when the inflammation subsides. It has been shown that inactivation of SIRT1 and SIRT6 allows sustained acetylation and activation of HIF-1α, which promotes the expression of glycolytic enzymes (54, 114). These data suggest that both SIRT1 and SIRT6 deficiency are major players in the Warburg metabolic switch activated by the fructose-uric acid metabolism.

CLINICAL CONDITIONS ASSOCIATED WITH FRUCTOSE METABOLIM, URIC ACID SYNTHESIS, AND WITH SIRTUIN DEFICIENCY

The PFU pathway is thought to play a role in the development of hypertension, metabolic syndrome, acute and chronic kidney disease, and NAFLD. Interestingly, SIRT1 deficiency has also been linked with the same conditions (Table 2).

Table 2.

SIRT 1 deficiency in the pathogenesis of disease states related to fructose-uric acid metabolism

Disease Conditions Associated with Polyol-Fructose-Uric Acid Pathway Effects of SIRT1 Deficiency of Pathophysiologic Relevance (References)
Hypertension Impaired endothelial vasodilatation (SIRT1 deficiency) (115,116)
↑ Angiotensin II type 1 R (117)
Oxidative stress and perivascular infiltration of immune cells associated with SIRT 3 deficiency (118)
Increased immune reactivity (55, 105,106)
Chronic kidney disease Proinflammatory and profibrotic reactivity
Stimulation of TGFβ and epithelial mesenchymal transition* (119121)
Acute kidney injury Aggravates mitochondrial oxidative stress (SIRT 1 overexpression improves recovery from AKI activating PGC1α) (122,123)
NAFLD Increased triglycerides, reduced lipid oxidation, increased oxidative stress, leptin resistance (34, 42,43, 47, 86,87)
Metabolic syndrome Increased lipogenesis, reduced lipid mobilization, insulin resistance (63, 79)

AKI, acute kidney injury; NAFLD, nonalcoholic fatty liver disease; PGC1, peroxisome proliferator-activated receptor-γ coactivator. *Data in experimental vitreoretinopathy (121).

Hypertension and Endothelial Dysfunction

Both fructose intake and hyperuricemia have been reported to be associated with the development of primary hypertension in humans. The mechanisms that play a role include stimulation of oxidative stress, reduction in nitric oxide bioavailability, and the activation of the renin-angiotensin aldosterone system (124). Studies have shown that uric acid upregulates angiotensinogen, angiotensin-converting enzyme, angiotensin II type I receptor (AT1R) and increases angiotensin II levels that were ameliorated with the antioxidant tempol (125, 126). The proinflammatory reactivity of uric acid, discussed earlier, stimulates the prorenin receptor, and contributes to establish hypertension and salt sensitivity (127). Consistent with these observations, the recent CARDIA study that followed 3,657 patients for 20 years found that high uric acid in young adulthood increasing overtime predicted the development of higher blood pressure and increased incidence of cardiovascular disease (128).

Hypertension and endothelial dysfunction also result from deficiency of SIRT1, SIRT3, and SIRT6 induced with high fructose intake (36, 129). Dietary fructose suppresses SIRT1 expression in vascular smooth muscle cells and impairs vasodilatation, both of which can be reversed by the SIRT1 agonist, resveratrol (115). SIRT1 has several antihypertensive effects. First, it suppresses immune reactivity (55, 105, 106) that is recognized to be prohypertensive (130). SIRT1 also downregulates expression of AT1R (117) and upregulates endothelial NO by deacetylating endothelial NO synthase (115, 116). Consistent with these findings, maternal feeding with a high-fructose diet contributes to the development of hypertension in the offspring, a finding attributed to a reduction in SIRT1 expression and upregulation of the expression of AT1R (131, 132).

The relation between hypertension, NAD+ depletion, and SIRT3 deficiency has been investigated by Dikalova et al. (118). They showed that SIRT3 inactivity resulted in hyperacetylation of superoxide dismutase, increase in superoxide levels, increase in HIF1α, with activation of NF-κB and inflammasome pathways and infiltration of T cells in the kidney. They further showed that increasing SIRT3 counteracted these manifestations.

SIRT6 is another NAD+-dependent deacetylase that is reduced in experimental models of hypertension induced by angiotensin II and DOCA-salt administration. Studies in endothelial-specific SIRT6 KO mice have shown that SIRT6 induces a positive regulation of the GATA binding protein 5 (GATA5 gene) by deacetylating histone H3K9, and this modification inhibits a transcriptional repressor. Conversely, overexpression of SIRT6 prevented experimental hypertension (133). Therefore, SIRT1, SIRT3, and SIRT6 deficiencies likely play a central role in the prohypertensive effects associated with fructose and uric acid metabolism.

Metabolic syndrome.

The PFU pathway is known to be associated with metabolic syndrome (insulin resistance, hypertension, dyslipidemia, obesity) (134). Similarly, as discussed earlier, sirtuin deficiency results in insulin resistance, increased lipid synthesis, and reduced fatty lipid oxidation and hypertension.

Kidney disease: acute and chronic.

Experimental studies and pilot clinical trials have supported a role for hyperuricemia in kidney injury. Uric acid induces renal inflammation by activating NF-κB in tubular cells (135) and experimental diabetic nephropathy is worsened by uric acid stimulation of NLRP3 inflammasome (136). Fructose metabolism has been shown to be involved in diabetic nephropathy due to activation of the PFU pathway (6). Recently, the beneficial effects of SGLT2 inhibition have been related to the induced increment of SIRT1 and HIF2α signaling resulting from this therapy (137). Nevertheless, the increase in serum uric acid with impairment in renal function has made it difficult to separate cause and effect and two recent well-powered clinical trials did not show benefit of lowering serum uric acid in ameliorating renal disease progression (12, 13). Potential explanations for lack of benefit and the identification of subgroups of chronic kidney disease in which lowering of uric acid may be of benefit have been recently reviewed (15).

Based on the prior discussion, an alternative explanation for the negative results is that metabolic and inflammatory effects of hyperuricemia would manifest only in those patients in whom NAD+ levels, and consequently sirtuin levels, are depleted. Indeed, sirtuins are widely expressed in both glomeruli and tubular cells, and the adverse effects derived from SIRT1 deficiency in the kidney are well known (119, 120). The protective effects of NAD+ generation have been shown by Zheng et al. (138) who found that NAM administration blocks TGFβ-induced fibrosis and inflammatory changes in the unilateral ureteral obstruction model. Although not examined in the kidney, SIRT1-induced deacetylation of SMAD5 might inhibit epithelial-mesenchymal transition, as shown in proliferative retinopathy (121).

NAD+ and sirtuins also protect against acute kidney injury (AKI) (122). PARP-1 KO mice, with suppressed NAD+ consumption, are resistant to ischemia-reperfusion injury (139). Blockade of fructokinase in the PFU pathway (140) and stimulation of SIRT1 both ameliorate AKI whereas SIRT1 depletion and increasing uric acid levels aggravate ischemic AKI (122, 141, 142).

Recent investigations have further emphasized that NAD+ and sirtuin abundance are safeguards of kidney health. Poyan-Mehr et al. (143) found impaired NAD+ synthesis in AKI in humans that is improved by oral NAM administration. Yasuda et al. (144) treated diabetic mice with nicotinamide mononucleotide (NMN) and found that upregulation of SIRT1 obtained with activation of the NAD+ salvage pathway improved diabetic nephropathy

Although there are other reasons (15, 145), we propose that variability of NAD+ and sirtuins activity could also explain the lack of benefit of lowering uric acid in studies of CKD (Fig. 2). It remains possible that the adverse effects attributed to hyperuricemia could be related to the severity of sirtuin’s deficiency, from the duration of NAD+ depletion and turnover, rather than a consequence of the serum uric acid level. Indeed, the half-life of NAD+ ranges from 15 min to 15 h (146) and the turnover and bioavailability of NAD+ have a severalfold range (79) depending on the balance between the NAD+ consumption, the NAD+/NADH ratio and the homeostatic response of NAD+ synthesis in de novo and salvage pathways.

Figure 2.

Figure 2.

Clinical conditions resulting from reduced SIRT1 activity. NAD+ depletion occurring from the synthesis and metabolism of fructose with the generation of uric acid may be compensated by NAD+ regeneration resulting from the activation of the de novo synthesis and by the salvage pathway. If reduced NAD+ is incompletely corrected, sirtuin deficiency could drive metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), acute and chronic kidney disease, and hypertension.

TREATMENT OPTIONS FOR CORRECTING SIRTUIN DEFICIENCY

Increase in sirtuins’ activity may be induced by sirtuin boosters and by treatments directed to increase NAD+. Resveratrol and STAC SRT2104 are sirtuin-activating compounds that have been used in clinical trials of obesity, diabetes, and NAFLD to increase SIRT1 but with inconsistent results (147149). Resveratrol improves inflammation and reduces uric acid levels because of downregulation of renal uric acid transporters (150). Resveratrol also activates AMPK in a SIRT1-dependent manner, improves mitochondrial function in vitro and in vivo (31), and increases the expression and enzymatic activity of eNOS in endothelial cells preventing eNOS uncoupling (32). SIRT1 agonists increase antioxidant defenses via a variety of mechanisms (30) but, to our knowledge, have not been used in clinical trials to improve the adverse effects of the fructose and uric acid. Sirtuins may also be increased indirectly by SGLT2 inhibitors (151) and directly by metformin (152), which may play a role in the beneficial outcomes of these compounds in patients with diabetes.

Sirtuin deficiency resulting from NAD+ depletion can also be corrected by increasing NAD+ bioavailability. This requires sufficient niacin and tryptophan in the diet to generate NAD+ from tryptophan, and this is aided by vitamins B3 (nicotinamide, nicotinic acid, and nicotinamide riboside) and B6 (pyridoxal, pyridoxine, and pyridoxamine) (153).

An increase in NAD+ may also be obtained by pharmacological suppression of NAD+ consumption and by supplementing NAD+ precursors. As discussed earlier, NAD+ is consumed not only by sirtuins but also by PARP-1 and CD38 (Fig. 2). Pharmacological inhibition of PARP-1 and CD38 preserves NAD+ for sirtuin activity (154). A similar benefit may occur by inhibiting the PFU pathway, which is expected to increase the NAD+/NADH ratio and sirtuin-induced deacetylation (Fig. 1). Inhibition of aldose reductase in the PFU pathway ameliorated oxidative stress in streptozotocin-induced diabetes (155). NAD+ can also be increased by activation of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the salvage pathway (156) or by NAD(P)H-quinone oxidoreductase 1, an enzyme that consumes NADH for the metabolism of quinones and, therefore, increases the NAD+/NADH ratio (157). However, these latter approaches are potentially dangerous because of interference with important cell signaling pathways (158).

Currently, the most promising strategy to increase NAD+ is the administration of NAD+ precursors (149). NMN supplementation improves heart failure in mice associated with an increase in SIRT1 and SIRT3 (159). Nicotinic acid, nicotinamide (NAM), nicotinamide riboside (NR), and nicotinic acid riboside (NAR) are NAD+ precursors that generate NAD+ and release NAM in the circulation. However, nicotinic acid is rarely used as it can cause severe flushing due to activation of G protein-coupled receptor GPR109A. NAM is a negative regulator of sirtuins, and high doses of NAM may actually inhibit sirtuins’ activity.

The pharmacokinetic profile of NR offers the highest levels of NAD+ after oral administration with best safety data (160). Combining NR with pterostilbene, a natural analog of resveratrol with increased absorption and half-life, has also been proposed (161). However, the best compound or combination of compounds and optimal doses to prevent and treat sirtuin deficiency require additional studies.

CONCLUSIONS

We posit that injurious collateral effects of fructose and hyperuricemia may be mediated, at least in part, by deficiency in sirtuin activity, particularly SIRT1 deficiency, resulting from consumption of NAD+ and reduction in the NAD+/NADH ratio. Investigation of the NAD+ and SIRT1 levels and their association with serum uric acid levels may clarify conflicting clinical results of treating hyperuricemia. Increasing NAD+ levels with the administration of NAD+ precursors, such as nicotinamide riboside, deserve to be tried for the prevention and correction of metabolic dysfunction and disease conditions associated with fructose metabolism and hyperuricemia.

Perspectives and Significance

Adverse effects of fructose metabolism and hyperuricemia may be due to deficiency of sirtuin deacetylases that result from uric acid-induced NAD+ consumption and reduction of the NAD+/NADH ratio in the polyol-fructose-uric acid pathway. Treatments directed to increase NAD+ and sirtuin abundance may prevent and correct injurious outcomes of hyperuricemia.

GRANTS

R. J. Johnson and M. A. Lanaspa were supported by National Institutes of Health Grants 1RO1DK109408-01A1 (to R.J.J.), RO1 DK108859-01 (to R.J.J.), and Veterans Affairs Merit BXI01BX004511 (to R.J.J.). Research in L. G. Sanchez-Lozada and F. E. García-Arroyo was supported by Direct Expenditure Funds authorized to the Basic Research Subdirectorate of the National Institute of Cardiology Ignacio Chávez. Research in B. Rodriguez-Iturbe was supported by Grants S1-2001001097 and 2005000283 (FONACYT, Venezuela) and by Grants 803 and 1093 (IVIC, Venezuela).

DISCLOSURES

B. Rodriguez-Iturbe and F. E. Garcia-Arroyo have no conflicts of interest to declare. L. G. Sánchez-Lozada, M. A. Lanaspa, and R. J. Johnson have equity in a start-up company developing fructokinase inhibitors (Colorado Research Partners LLC). R. J. Johnson and T. Nakagawa also have equity with XORTX Therapeutics that is developing novel xanthine oxidase inhibitors. R. J. Johnson has also received honoraria from Horizon Pharmaceuticals, Inc.

AUTHOR CONTRIBUTIONS

B.R.-I. and L.G.S.-L. conceived and designed research; F.E.G.-A. performed experiments; B.R.-I., R.J.J., and L.G.S.-L. analyzed data; B.R.-I., R.J.J., F.E.G.-A., and L.G.S.-L. interpreted results of experiments; B.R.-I. and L.G.S.-L. prepared figures; B.R.-I. and L.G.S.-L. drafted manuscript; B.R.-I., R.J.J., M.A.L., T.N., F.E.G.-A., and L.G.S.-L. edited and revised manuscript; B.R.-I., R.J.J., M.A.L., T.N., F.E.G.-A., and L.G.S.-L. approved final version of manuscript.

ACKNOWLEDGMENTS

Present address of B. Rodriguez-Iturbe and L. G. Sánchez-Lozada: Juan Badiano 1, Seccion XVI, Municipio Tlalpan, Edificio Santiago Galas, CP 14080, Mexico City, Mexico.

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