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Home , Carbohydrate metabolism, Fructolysis, Gluconeogenesis

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Fructose Production and in the

Takahiko Nakagawa,1,2 Richard J. Johnson,3 Ana Andres-Hernando,3 Carlos Roncal-Jimenez,3 Laura G. Sanchez-Lozada ,4 Dean R. Tolan,5 and Miguel A. Lanaspa 3

1Department of Nephrology, Rakuwakai Otowa Hospital, Kyoto, Japan 2Department of , Shiga University of Medical Science, Shiga, Japan 3Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado 4Department of Cardio-Renal Physiopathology, National Institute of Cardiology Ignacio Chavez, Mexico City, Mexico 5Department of Biology, Boston University, Boston, Massachusetts

ABSTRACT Understanding metabolism might provide insights to renal pathophysiology. To the metabolism of endogenous fructose support systemic concentration, the proximal tubular cells reabsorb fructose as a can slow the development and progres- substrate for . However, in instances when fructose intake is excessive, sion of kidney injury. fructose metabolism is costly, resulting in energy depletion, uric acid generation, inflam- Fructose biology is complex because mation, and fibrosis in the kidney. A recent scientific advance is the discovery that fruc- fructose metabolism may be associated tose can be endogenously produced from glucose under pathologic conditions, not only with beneficial physiologic responses and in kidney diseases, but also in , in cardiac hypertrophy, and with dehydration. pathologic responses. Here, we discuss the Why humans have such a deleterious mechanism to produce fructose is unknown, but it various roles of fructose in the kidney. may relate to an evolutionary benefit in the past. In this article, we aim to illuminate the roles of fructose as it relates to gluconeogenesis and fructoneogenesis in the kidney.

JASN 31: 898–906, 2020. doi: https://doi.org/10.1681/ASN.2019101015 CLINICAL ASSOCIATIONS OF FRUCTOSE WITH KIDNEY DISEASES

Fructose is a simple sugar in that of serum glucose,8 to support fetal organ Fructose, as a component of high- has a role in storage of fat and , development,9 and to offer protection fructose corn syrup or table sugar, is a development of resistance, and from hypoxic insults.10 major component in most sugar-sweetened an increase in sodium reabsorption, all In modern society, dietary sugars, soft drinks. The dramatic increase in of which are likely survival processes for particularly fructose, have emerged as fructose consumption has stimulated during time of food shortage.1 culprits for the current epidemic of obe- a heated debate over the potential danger fi 11 The freshwater pacu sh actively feasts sity, diabetes, and . of sugar-sweetened beverages.22,23 on ripe fruits that have fallen into the The rise in fructose consumption over In 2009, Bomback et al.24 combined river and becomes fat in the rainy sea- the last century has paralleled the rising cross-sectional and longitudinal analy- son.2 To increase their fat stores before prevalence of obesity, diabetes, and kid- ses to evaluate the association between beginning their migration, birds that mi- ney diseases, leading to the hypothesis CKD and sugar-sweetened beverages, grate long distances develop a seasonal that excessive fructose might be a causal but found no association between sugar- dietary preference for fruits.3 Hibernat- factor for the development of kidney dis- sweetened soda and incidence or preva- via ing mammals, such as bears and ground ease. One proposed mechanism is the lence of CKD. Although the outcomes of squirrels, use their accumulated fat as an metabolism of fructose () be- energy supply during winter.4,5 Likewise, cause it can result in intracellular energy for early primates, fresh fruits were the depletion, mitochondrial oxidative Published online ahead of print. Publication date available at www.jasn.org. main dietary staple.6,7 Fructose remains , and the production of inflamma- an important nutrient for humans and tory mediators such as uric acid.12 Re- Correspondence: Dr. Takahiko Nakagawa, Depart- ment of Nephrology, Rakuwakai Otowa Hospital, 2 wild animals because the kidney, the cently, it has emerged that fructose can Otowa-Chinji-cho, Yamashina-ku, Kyoto, Japan. Email: placenta, and hypoxic tissues use it as be endogenously produced in humans13,14 [email protected] 15–21 a substrate for gluconeogenesis to and nonhuman animals, particularly Copyright © 2020 by the American Society of maintain physiologic concentrations in diseased kidneys, and that blocking Nephrology

898 ISSN : 1046-6673/3105-898 JASN 31: 898–906, 2020 www.jasn.org REVIEW this study should be noted, renal effects by Benoy and Elliott32 showing that rat depends on the level, because it are unlikely to be observed at a dosage of kidney slices were capable of producing is slower under anaerobic conditions only one sugar-sweetened beverage per glucose in response to pyruvate and lac- compared with aerobic conditions.43 Glu- day.25 Similarly, Lin and Curhan26 identi- tate. A study using hepatectomized dogs coneogenesis is driven by the activation of fied 3318 women participating in the subsequently confirmed this phenome- phosphoenolpyruvate carboxykinase, Nurses’ Health Study with data on soda non by demonstrating that blood sugar of the glucose 6- intake and albuminuria and found no as- declined more rapidly with removal of system, and fructose bisphosphatase ex- sociation between daily consumption of the kidneys.33 Reinecke and Hauser34 clusively in the proximal tubular cells,44,45 one or more serving and incidence of also showed in dogs that serum glucose but not in the distal nephron46,47 (Figure 2). CKD;but,giventhatonly3%ofpartici- concentrationintherenalveinwas The proximal straight tubule is a pri- pants had this level of consumption, this higher than in the renal artery. Three de- mary site for fructose metabolism. also might account for the negative results. cades later, research demonstrated that There, 5, expressed In contrast, Saldana et al.27 examined the rat kidney is capable of producing on the apical side of the cell membrane, the effect of higher doses in a case-control approximately 26% of serum glucose mediates absorption of urinary fructose, study, and found that an intake of two or in the normal fed state, and that renal which is then metabolized by fructoki- more sugar-sweetened beverages per glucose release increases 46% after nase in the .48 However, fructose day was associated with an increased starvation35; the human kidney similarly metabolism is not restricted to the prox- incidence of kidney disease. Likewise, provides approximately 45% of total imal straight tubule; it has also been Shoham et al.28 found that consumption blood glucose after .8 Interest- documented in the proximal convoluted of two or more sugar-sweetened beverages ingly, diabetes also increases renal glucose tubule (Figure 1). In fact, the proximal per day was associated with a higher level release by 360% in rats and 300% in hu- convoluted tubule expresses , of urinary albumin excretion compared mans compared with the nondiabetic as well as , which is readily in- with consumption of less than two sugar- condition.35,36 In metabolic acidosis in duced.48 A lack of aldolase B in patients sweetened beverages per day. More re- the rat, gluconeogenesis has also been with hereditary fructose intolerance cau- cently, a 2019 study of a community-based found to be activated in the proximal tu- ses fructose 1-phosphate accumulation in cohort of black Americans also showed that bules, as opposed to the .37,38 the proximal convoluted tubule.49 a higher sugar-sweetened beverage con- Renal gluconeogenesis may result sumption was associated with signifi- from classic substrates such as lactate, Is Less Activated in the cantly greater odds of incident CKD.29 , , and pyruvate, but Proximal Tubules Moreover, in an intervention study in fructose appears to be the preferred sub- In the late 20th century, several researchers which a low-fructose was administered strate, based on the speed and efficiency demonstrated that the potential for glycol- to participants with CKD, researchers ob- of the reaction.39,40 In 1961, by using in ysis is very low in the proximal tubules served a reduction in BP and systemic situ perfusion in the rat, Salomon et al.41 compared with other parts of the nephron, inflammation.30 directly measured the arteriovenous dif- including from the medullary ascend- Although the possible association of ference of fructose and glucose concen- ing limb to the medullary collecting sugar-sweetened beverages with kidney trations after bolus infusion of 25 mg of tubule. For example, key enzymes for disease may reflect the sugar (and espe- fructose into the peripheral vessels. They glycolysis—, phosphofructo- cially fructose) content, sugar-sweetened found that decreases in fructose concen- kinase, and —are min- beverages also contain substantial tration on the passage of blood through imally expressed in proximal tubular amount of phosphorus, which could be the kidney—about 19% on average— epithelial cells.38,50 Hexokinase, the gate- an alternative risk factor for obesity, vas- were accompanied by equivalent in- way of glucose metabolism, phos- cular injury, systemic hypertension, and creases in renal venous glucose.41 In phorylates glucose to glucose 6-phosphate kidney disease.31 1982, Björkman et al.42 found that intrave- and is least active in the proximal tubules nous infusion of fructose at 2 mmol/min relative to the entire nephron. In turn, the for 135 minutes into the peripheral vein distal nephron shows higher activity of FRUCTOSE METABOLISM IN of humans resulted in a constant rise in glycolytic enzymes. Hexokinase activity NORMAL KIDNEY glucose concentration in the renal vein is 15 times higher in the thick ascending (0.1760.05 mmol/L); they also indicated limb of the loop of Henle than in the prox- Fructose Is Physiologically that 20% of intravenously infused fruc- imal tubules.51 Likewise, pyruvate kinase, Converted to Glucose in the Kidney tose was taken up by the kidney and that an enzyme catalyzing another irreversible In the mid- to late 20th century, several the net glucose release from the kidney step in the glycolytic pathway, is highly investigators intensively studied glucose could be derived from 55% of the net re- activated in the collecting ducts but not metabolism in the kidney. The first pa- nal uptake of fructose. Interestingly, fruc- in the proximal tubules.38 per documenting renal gluconeogenesis, tose is metabolized into lactate faster Glycolysis contributes to only 4% of to our knowledge, was a study in 1937 than is glucose. However, this reaction the renal ATP produced under aerobic

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Figure 1. The S1 and S2 of the proximal tubular cells cooporately metabolize fructose. Both proximal convoluted tubules (PCT) and proximal straight tubules (PST) participate in fructose (Fru) metabolism. AldoB, aldolase B; DHAP, dihydroxyacetate phosphate; FBPase, fructose 1,6-bisphosphatase; FK, fructokinase; Fru1P, fructose 1-phosphate; Fru1,6P2, fructose 1,6 bisphosphate; Glc, glucose; Glc6P, glucose 6-phosphate; G3P; glyeraldehyde 3-phosphate; G6Pase, glucose 6-phosphatase; Glut2/5, glucose transporter 2/5. conditions in the proximal tubular ENDOGENOUSLY PRODUCED thekidneyappearstobebeneficial in cells.38 The glucose reabsorption rate in FRUCTOSE IS A RISK FACTOR FOR slowing the development of renal disease the proximal tubules is 35 pmol/min per RENAL INJURY (Table 1). mm, whereas hexokinase activity is ap- proximately 2 pmol/min per mm, sug- A recent scientific advance has been the Diabetic Nephropathy gesting that only 5% of glucose entering discovery that the kidney and several In diabetes, the polyol pathway may play the cell is phosphorylated in the proxi- other organs are capable of endoge- a key role in the development of diabetic mal convoluted tubules.52 The large por- nously producing fructose. The key complications.56 Although renal aldose tion of glucose is not physiologically mechanism is the activation of the polyol reductase expression is enhanced in used as an energy source,53 but rather pathway, in which re- diabetes,16,57,58 the functional role of is released into the peritubular capillary duces glucose to , which is then aldose reductase was implicated by via glucose transporter 2 in the basolat- oxidized by to the finding that a transgenic mouse line eral membrane of the proximal cells.54 fructose (Figure 2). Importantly, studies carrying human aldose reductase cDNA However, Chamberlin et al.55 proposed with mice lacking the fructokinase gene developed thrombosis in renal vessels that glycolysis met the energy needs of showed that blocking the metabolism with some collagen deposits in Bowman’s distal portions of nephron. (fructolysis) of endogenous fructose in capsule—developments that partially

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Figure 2. Both fructolysis and fructogenesis occuring in the kidney are modulated by uric acid. AR, aldose reductase; FA, ;

FK, fructokinase; Fru, fructose; Fru6P, fructose 6-phosphate; Fru1,6P2, fructose 1,6 bisphosphate; DHAP, dihydroxyacetate phosphate; Glc, glucose; Glc6P, glucose 6-phosphate; G3P; glyeraldehyde 3-phosphate; OXPHOS, mitochondrial oxidative phosphorylation; PEP, phosphoenolpyruvate; PPP, pentose phosphate pathway; SDH, sorbitol dehydrogenase; TCA, tricarboxylic acid cycle. resembled the histologic changes of issue would be to use aldose reductase the development of AKI in mice and hu- human diabetic nephropathy.59 We inhibitors in patients with diabetes. The mans.19 Investigators reported that recently found that streptozotocin- Aldose Reductase Inhibitor-Diabetes seven of 12 pediatric patients developed induced diabetic mice had higher levels Complications Trial Study Group61 re- AKI after undergoing cardiac bypass sur- of fructose and urate in the kidney ported finding that inhibition of aldose gery, and that those with AKI had signif- compared with nondiabetic mice, and reductase with epalrestat could slow icantly higher concentrations of fructose that diabetic mice lacking fructokinase the progression of diabetic nephropa- in the urine. Given that these patients were protected and exhibited less albu- thy, whereas other studies did not.62 were in the early postoperative period, minuria, better renal function, and less We recommend further trials to deter- fructose in the urine unlikely originated tubular injury.16 mine if aldose reductase inhibitors from the hospital diet, but was likely en- People with diabetes have higher lev- might provide benefitindiabetic dogenously produced, perhaps in the els of fructose in the serum and urine,60 nephropathy. kidney. The researchers investigated this which is suggestive of endogenous fruc- possibility in mice subjected to ischemia- tose production. However, the patho- Other Kidney Diseases of the kidney, finding logic role of the polyol pathway remains There is evidence that, in addition to di- that wild-type mice with AKI developed elusive. One practical way to address this abetes, fructoneogenesis contributes to severe tubular injury associated with ac- tivation of the polyol pathway, as evi- Table 1. Type of diseases which are ameliorated by fructokinase deficiency denced by high levels of aldose reductase, sorbitol, and endogenous fructose. In con- Type of Disease Reference trast, knockout mice lacking fructokinase 16 Diabetic nephropathy in streptozotocin-induced diabetic mice showed partial protection, with less tubular AKI in mice with renal ischemia reperfusion 19 injury and improved renal function. They Aging kidney in aged mice 18 Dehydration-associated kidney injury in mice with heat 63 also demonstrated a deleterious role for Cardiac hypertrophy in mice with 1K1C 20 the metabolism of endogenous fructose Metabolic syndrome in mice with fructose- 90 in mice with radiocontrast-induced Metabolic syndrome in mice with high salt intake 15 nephropathy.19 Intestinal cancer in APC-deficient mice consuming fructose diet 92 Recurrent heat stress and dehydra- 1K1C, one-kidney, one-clip; APC, adenomatous polyposis coli. tion can also cause CKD in mice,63 and

JASN 31: 898–906, 2020 Fructose Production and Metabolism 901 REVIEW www.jasn.org this may be relevant to epidemics of this reaction, fructokinase activation ferment glucose into lactate, even in the CKD that are occurring in Central requires a phosphate, which reduces in- presence of sufficient oxygen.75,76 America, Sri Lanka, and India.64 tracellular phosphate levels and depletes Recently, several studies demon- Chronic, recurrent dehydration also re- ATP.12 The rapid reduction of phosphate strated the Warburg effect in the diseased sults in aldose reductase activation in activates AMP deaminase, which in turn kidney, in which aerobic glycolysis would both the kidney and hypothalamus, drives adenine turnover and provide a mechanism for renal fibrosis in leading to fructoneogenesis at both stimulates urate production.11,65,66 As several types of kidney diseases (Figure 3).77 sites.21,63 Importantly, mice lacking such, an excess amount of fructose either In fact, either pharmaceutic blocking of fructokinase were largely protected from diet or from endogenous produc- glycolysis or switching aerobic phosphory- from CKD induced by repeated heat tion could result in a high amount of in- lation back to oxidative phosphorylation stress and dehydration.63 tracellular uric acid.11 inhibits renal fibrosis from developing in Finally, senescence (aging) changes Findings from studies in cultured the obstructed kidney.78 Importantly, ei- in the kidney may also be mediated by cells or in models demonstrate ther fructose or glucose could be an en- fructokinase activation. Aging wild- multiple potential pathologic roles of ergy source for the Warburg effect and type mice are known to exhibit renal uric acid. These include causing endo- the fructose–uric acid pathway could be dysfunction characterized by an in- thelial dysfunction, vascular injury, and a mechanism to drive aerobic glycolysis crease in urinary albumin excretion, inflammation that lead to glomerular in the development of renal fibrosis.79,80 glomerular collagen IV deposition, hypertension, tubulointerstitial injury, AKI can be associated with the release and tubulointerstitial injury. How- and an elevation in systemic BP.11,66–70 of inflammatory cytokines mediated ever, researchers demonstrated these Biologic mechanisms include a reduction by activation of the transcription factor injuries were ameliorated in frucokinase in endothelial nitric oxide, oxidative stress, NF-kB, and one study suggested that en- knockout mice.18 and renin-angiotensin activation, all of dogenously produced fructose and its which may predispose to hypertension.71 metabolism via fructokinase can result Nonkidney Diseases as a Target of Uric acid also modulates metabolic status in such an NF-kB–mediated inflamma- Endogenous Fructose: Cardiac in response to fructose and increases the tory response.19 Thereisevidenceindi- Hypertrophy risk for animals to develop insulin resis- abetic mice that tubular injury is also In addition to the kidney, other organs tance and metabolic syndrome.66 It can associated with inflammation involving likely produce fructose. Recently, also feed back to amplify both aldose re- inflammatory cytokines regulated by Mirtschink et al.20 showed that the heart, ductase and fructokinase expression.72 NF-kB.16 As in the AKI model, studies particularly the cardiac myocyte, is capa- Although debate on the pathologic role in a model of diabetic nephropathy ble of endogenous fructose production, of uric acid continues, accumulating ev- found that the expression of inflammatory and that the fructose generated was idence suggests that it likely has a role in cytokines (IL-1b,IL-6,andmonocyteche- involved in pathologic cardiac hyper- hypertension, , and moattractant -1) and NF-kBactiva- trophy. Specifically, they identified CKD.73,74 tionwerealsodependentonendogenous fructokinase as a hypoxia-inducible factor fructose and fructose metabolism in a 1a–mediated factor that was activated in Kidney Disease model of diabetic nephropathy.16,81,82 mouse models of cardiac hypertrophy in- One effect of uric acid is to stimulate mi- Fructose also stimulates endothelial duced by hypertension.20 Importantly, tochondrial oxidative stress that causes a cells to induce intercellular adhesion fructokinase knockout mice were protec- decrease in activity of aconitase, an en- molecule-1.67 The induction of oxidative ted from the cardiac remodeling in these zyme of the tricarboxylic acid cycle that stress by fructose can also “uncouple” en- models. The authors also reported converts citrate to isocitrate and discon- dothelial nitric oxide synthase, resulting in finding upregulation of fructokinase nects fructose metabolism from mito- a reduction in nitric oxide availability.83–85 in cardiomyocytes obtained from bi- chondrial respiration.65 As a result, In addition, several transcription factors opsies of patients with hypertrophic phosphates, which are metabolites of have been shown to be involved in fruc- cardiomyopathy. fructose 1-phosphate catalyzed by aldol- tose metabolism, including Sterol reg- ase B, enter the glycolytic pathway distal ulatory element-binding protein 1 to and drive aerobic (SREBP1c), -responsive PATHOPHYSIOLOGY OF glycolysis, with the pathologic activation element-binding protein (ChREBP), FRUCTOSE of gluconeogenesis and . This and peroxisome proliferators-activated results in the production of glucose, receptor-g (PPAR-g) coactivator-1a Potential Role for Uric Acid glycogen, lactate, and that (PCG-1a), and these factors are currently Fructokinase (also known as ketohexoki- creates the “Warburg effect” (Figure 2). considered to be involved in fructose- nase), which catalyzes the first step of fruc- In 1924, Otto Heinrich Warburg initially mediated lipogenesis.86 Further studies tose metabolism, phosphorylates fructose described that cancer cells, as opposed to are needed to clarify their roles in to produce fructose 1-phosphate. During normal cells, exhibit a unique ability to inflammation.

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Figure 3. Both dietary and endogenously produced fructose cause CKD, nonalcoholic fatty liver disease (NAFLD) and metabolic syn- drome. FK, fructokinase; NO, nitric oxide.

Metabolic Syndrome and Insulin metabolic syndrome. Interestingly, some insulin resistance results from im- Resistance blocking uric acid production partially paired delivery of glucose that results By suppressing mitochondrial oxidative ameliorated the development of hyper- when endothelian dysfunction causes phosphorylation, fructose stimulates tension, , and insu- impaired peripheral perfusion.87,88 glycolysis, gluconeogenesis, and lipo- lin resistance in fructose-fed rats,11,66 Fructose-induced endothelial dysfunction genesis. Fructokinase, which is the gate- suggesting that uric acid plays a role in due to endothelial nitric oxide synthase keeper because it catalyzes the first step fructose-induced metabolic syndrome uncoupling is likely involved in insulin re- of fructose metabolism, is activated in a (Figure 3). sistance in addition to dysregulation of fructose dose–dependent manner without Insulin resistance is a phenotype ex- synthesis (Figure 3).67 any negative regulation. Consequently, hibiting a decreased uptake of glucose the production of several metabolites— into insulin-dependent tissues, such as Nonalcoholic Fatty Liver Disease including glucose, lipid, and glycogen— skeletal muscle. Common mechanisms Nonalcoholic fatty liver disease is a he- are enhanced, thereby contributing to the include an impairment in insulin signal- patic phenotype of metabolic syndrome, development of obesity, diabetes, and ing associated with lipid alterations, but and experimental and clinical studies

JASN 31: 898–906, 2020 Fructose Production and Metabolism 903 REVIEW www.jasn.org suggestthatfructoseisoneofitsstrongest the submitted work. In addition, Dr. Johnson has a of definite interest for the nephrologist. Kid- – risk factors.89 Fructokinase has two iso- US Patent number 9,387,245 issued, a US Patent ney Int 83: 207 212, 2013 5. Carey HV, Andrews MT, Martin SL: Mammalian forms: fructokinase-C and fructokinase-A. number 8,697,628 issued, a patent number PCT/US2011/046938 pending, and a patent hibernation: Cellular and molecular responses Interestingly, mice lacking both isoforms number PCT/US2011/046938 pending, as well to depressed metabolism and low tempera- are protected from fructose-induced fatty as inventorship status on US Patent number ture. Physiol Rev 83: 1153–1181, 2003 liver, whereas in mice with genetic deletion 8,557,831 for uric acid and insulin resistance and 6. Johnson RJ, Andrews P, Benner SA, Oliver W: of only fructokinase-A fatty liver is more US Patent number 9,155,740 for uric acid and di- Theodore E. Woodward award. The evolution of obesity: Insights from the mid-Miocene severe than in wild-type mice.90 This abetic nephropathy, and patent applications related fi to fructose metabolism and metabolic disease. [published correction appears in Trans Am nding is likely because fructokinase-C Dr. Johnson and Dr. Lanaspa have patents and pat- Clin Climatol Assoc 124: 294, 2013]. Trans causes rapid ATP degradation, whereas ent applications related to their discoveries that they Am Clin Climatol Assoc 121: 295–305; dis- fructokinase-A metabolizes fructose very assigned to the University of Colorado. Dr. Johnson, cussion 305–308, 2010 slowly, with relatively minimal ATP con- Dr. Lanaspa, and Dr. Tolan are members of and re- 7. Finch CE, Stanford CB: Meat-adaptive genes and the evolution of slower aging in humans. sumption. Hence, blocking fructokinase-A port equity with Colorado Research Partners LLC that is developing inhibitors of fructose metabolism Q Rev Biol 79: 3–50, 2004 actually increases the amount of fructose for the treatment of metabolic syndrome and kid- 8. Owen OE, Felig P, Morgan AP, Wahren J, available for metabolism by fructokinase-C. ney disease. Dr. Johnson and Dr. Nakagawa have Cahill GF Jr.: Liver and kidney metabolism The mechanism by which fructose several patent applications related to uric acid dis- during prolonged starvation. JClinInvest48: – stimulates de novo lipogenesis and blocks covered in the University of Floria and have equity 574 583, 1969 9. Kim J, Song G, Wu G, Bazer FW: Functional hepatic fatty acid oxidation is shown in in XORTX Therapeutics that is developing novel xanthine oxidase inhibitors. Dr. Nakagawa reports roles of fructose. Proc Natl Acad Sci U S A Figure 3. With fructose-induced hepatic grants from Fuji Yakuhin Co, grants from Suzuken, 109: E1619–E1628, 2012 lipogenesis, uric acid blocks aconitase; and grants from Teijin Pharma, outside the sub- 10. Park TJ, Reznick J, Peterson BL, Blass G, this causes citrate to accumulate and mitted work. In addition, Dr. Nakagawa has two Omerbašic D, Bennett NC, et al.: Fructose- move into the cytoplasm to stimulate patents; US8557831 and US9155740B2, both were driven glycolysis supports anoxia resistance in the naked mole-rat. Science 356: 307–311, 2017 ATP citrate lyase, activating lipogenesis. issued on October 13, 2015. Our docket number 11160-006UC2 is pending. Dr. Sanchez-Lozada 11. Nakagawa T, Tuttle KR, Short RA, Johnson There are several studies showing that reports grants from DANONE RESEARCH out- RJ: Hypothesis: Fructose-induced hyperuri- xanthine oxidase inhibitors could par- side the submitted work. Dr. Tolan reports per- cemia as a causal mechanism for the epi- tially reduce fatty liver in both fructose- sonal fees from Alnylam Pharmaceuticals, grants demic of the metabolic syndrome. Nat Clin – dependent and fructose-independent and personal fees from Colorado research Part- Pract Nephrol 1: 80 86, 2005 12. Mäenpää PH, Raivio KO, Kekomäki MP: Liver models of metabolic syndrome and non- ners, outside the submitted work, as well as several contracts and grants related to fructose metabo- adenine : Fructose-induced de- 65,91 alcoholic fatty liver disease. lism and metabolic disease. Dr. Andres-Hernando pletion and its effect on protein synthesis. and Dr. Roncal-Jimenez have nothing to disclose. Science 161: 1253–1254, 1968 13. Francey C, Cros J, Rosset R, Crézé C, Rey V, SUMMARY Stefanoni N, et al.: The extra-splanchnic fructose escape after ingestion of a fructose- FUNDING glucose drink: An exploratory study in healthy Fructose at physiologic concentrations is humans using a dual fructose isotope method. – predominantly metabolized to produce This work was supported in part by National Clin Nutr ESPEN 29: 125 132, 2019 glucose in the proximal tubular epithelial Institutes of Health grants R01DK108408 and 14. Hwang JJ, Jiang L, Hamza M, Dai F, Belfort- R01DK108859. DeAguiar R, Cline G, et al.: The human brain cells of the kidney. However, sustained produces fructose from glucose. JCI Insight exposure to excessive quantities of fruc- 2: e90508, 2017 tose likely induces fructolysis, resulting REFERENCES 15. Lanaspa MA, Kuwabara M, Andres-Hernando A, in significant ATP depletion and inflam- Li N, Cicerchi C, Jensen T, et al.: High salt intake mation, leading to tubular injury. Endog- causes leptin resistance and obesity in mice 1. Johnson RJ, Stenvinkel P, Andrews P, by stimulating endogenous fructose production enously produced fructose through renal Sanchez-Lozada LG, Nakagawa T, Gaucher and metabolism. Proc Natl Acad Sci U S A 115: fructoneogenesis, combined with subse- E, et al.: Fructose metabolism as a common 3138–3143, 2018 quent fructolysis, might be a mechanism evolutionary pathway of survival associ- 16.LanaspaMA,IshimotoT,CicerchiC,TamuraY, for progression of kidney disease. Impor- ated with climate change, food shortage and Roncal-Jimenez CA, Chen W, et al.: Endogenous – tantly, uric acid is often a mediator for fruc- droughts. J Intern Med 287: 252 262, 2020 fructose production and fructokinase activation ’ 2. Junk WJ: Temporary fat storage, an adapta- mediate renal injury in diabetic nephropathy. tose s adverse effects. Effects of fructose on tion of some fish species to the water level J Am Soc Nephrol 25: 2526–2538, 2014 other organ systems may also be involved fluctuations and related environmental changes 17. Lanaspa MA, Ishimoto T, Li N, Cicerchi C, in the development of kidney injury. oftheAmazonriver.Amazoniana 9: 315–351, Orlicky DJ, Ruzycki P, et al.: Endogenous 1985 fructose production and metabolism in the liver 3. Bairlein F: How to get fat: Nutritional contributes to the development of metabolic DISCLOSURES mechanisms of seasonal fat accumulation in syndrome [published correction appears in Nat migratory songbirds. Naturwissenschaften Commun 4: 2929, 2013]. Nat Commun 4: 2434, 89: 1–10, 2002 2013 Dr. Johnson reports personal fees from Eli Lilly 4. Stenvinkel P, Jani AH, Johnson RJ: Hiber- 18. Roncal-Jimenez CA, Ishimoto T, Lanaspa and personal fees from Horizon Pharma, outside nating bears (Ursidae): Metabolic magicians MA, Milagres T, Hernando AA, Jensen T,

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