Fructose and Uric Acid: Is There a Role in Endothelial Function?
- 943 Downloads
Population level data support that consumption of fructose and fructose-based sweeteners has dramatically increased and suggest that high dietary intake of fructose is an important factor in the development of the cardiorenal metabolic syndrome (CRS). The CRS is a constellation of cardiac, kidney and metabolic disorders including insulin resistance, obesity, metabolic dyslipidemia, high blood pressure, and evidence of early cardiac and kidney disease. The consequences of fructose metabolism may result in intracellular ATP depletion, increased uric acid production, oxidative stress, inflammation, and increased lipogenesis, which are associated with endothelial dysfunction. Endothelial dysfunction is an early manifestation of vascular disease and a driver for the development of CRS. A better understanding of fructose overconsumption in the development of CRS may provide new insights into pathogenesis and future therapeutic strategies.
KeywordsCardiorenal metabolic syndrome Nitric oxide Lipogenesis Insulin resistance Hypertension Oxidative stress Inflammation Estrogen
The authors would like to thank Brenda Hunter for her editorial assistance. This research was supported by National Institutes of Health grants HL-73101 and HL-107910 to J.R.S. and AG-040638 to A.W.-C. and the Veterans Affairs Merit System 0018 (J.R.S.) and CDA-2 (A.W.-C.).
Compliance with Ethics Guidelines
Conflict of Interest Guanghong Jia, Annayya R. Aroor, Adam T. Whaley-Connell, and James R. Sowers declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 6.Jindal A, Garcia-Touza M, Jindal N, et al. Diabetic kidney disease and the cardiorenal syndrome: old disease, new perspectives. Endocrinol Metab Clin N Am. 2013;42:789–808.Google Scholar
- 16.••Johnson RJ, Nakagawa T, Sanchez-Lozada LG, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013;62:3307–15. This study showed the major discovery that fructose-mediated generation of uric acid may have a causal role in diabetes and obesity, and provides new insights into pathogenesis and therapies for this important disease.PubMedPubMedCentralGoogle Scholar
- 17.•Sowers JR, Whaley-Connell A, Hayden MR. The role of overweight and obesity in the cardiorenal syndrome. Cardiorenal Med. 2011;1:5–12. This study revealed the potential mechanisms by which obesity and other metabolic abnormalities interact to promote heart and progressive kidney disease.PubMedPubMedCentralGoogle Scholar
- 19.Feinman RD, Fine EJ. Fructose in perspective. Nutr Metab (Lond). 2013;10:45.Google Scholar
- 21.••Chaudhary K, Malhotra K, Sowers J, Aroor A. Uric acid - key ingredient in the recipe for cardiorenal metabolic syndrome. Cardiorenal Med. 2013;3:208–20. This study also found that elevated serum levels of uric acid appear to contribute to impaired nitric oxide production/endothelial dysfunction, increased vascular stiffness, inappropriate activation of the renin-angiotensin-aldosterone system, enhanced oxidative stress, and maladaptive immune and inflammatory responses.PubMedPubMedCentralGoogle Scholar
- 25.Soltani Z, Rasheed K, Kapusta DR, Reisin E. Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal? Curr Hypertens Rev. 2013;15:175–81.Google Scholar
- 34.••Muniyappa R, Sowers JR. Endothelial insulin and IGF-1 receptors: when yes means NO. Diabetes. 2012;61:2225–7. This report also revealed that interventions aimed at downregulating IGF-1R expression may augment endothelial insulin sensitivity in the pathological states.PubMedPubMedCentralGoogle Scholar
- 37.•Muniyappa R, Sowers JR. Role of insulin resistance in endothelial dysfunction. Rev Endocr Metab Disord. 2013;14:5–12. This study revealed the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- atherogenic and anti-atherogenic actions of insulin.PubMedPubMedCentralGoogle Scholar
- 43.•Kim JA, Jang HJ, Martinez-Lemus LA, Sowers JR. Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. Am J Physiol Endocrinol Metab. 2012;302:E201–8. This report showed that Ang II-mediated impairment of vascular actions of insulin may help explain the role of Ang II as a link between insulin resistance and hypertension.PubMedGoogle Scholar
- 46.•Tran LT, Yuen VG, McNeill JH. The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol Cell Biochem. 2009;332:145–59. This study addressed the role of sympathetic nervous system overactivation, increased production of vasoconstrictors, such as endothelin-1 and angiotensin II, and prostanoids in the development of hypertension in fructose-fed rats.PubMedGoogle Scholar
- 47.•Manrique C, DeMarco VG, Aroor AR, et al. Obesity and insulin resistance induce early development of diastolic dysfunction in young female mice fed a Western diet. Endocrinology. 2013;154:3632–42. This report also revealed that higher aldosterone levels, in concert with insulin resistance, may promote myocardial stiffness and diastolic dysfunction in response to overnutrition in females.PubMedPubMedCentralGoogle Scholar
- 55.Lee SA, Kim EY, Jeon WK, et al. The inhibitory effect of raloxifene on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells is mediated through a ROS/p38 MAPK/CREB pathway to the up-regulation of heme oxygenase-1 independent of estrogen receptor. Biochimie. 2011;93:168–74.PubMedGoogle Scholar