Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes

Abdelmalek, Manal F.; Lazo, Mariana; Horská, Alena; Bonekamp, Susanne; Lipkin, Edward W.; Balasubramanyam, Ashok; Bantle, John P.; Johnson, Richard J.; Diehl, Anna Mae; Clark, Jeanne M.

doi:10.1002/hep.25741

Cited by 159 publications

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“…Accordingly, other mechanisms must account for the association between hyperuricemia and insulin resistance. Diet-induced insulin resistance is a possible explanation for the association between serum urate and insulin resistance (1,5). During consumption of high-carbohydrate diets, the liver is exposed to high portal vein concentrations of glucose and/or fructose, which cause elevation in hepatic organic phosphate esters and activation of the transcription factor ChREBP-Mlx (3,6).…”

Section: Discussionmentioning

confidence: 99%

“…1). However, whether dietary fructose contributes to hyperuricemia in liver disease remains debated (1,33,40).Studies in humans have reported low hepatic ATP in obesity (10) and inverse correlations between hepatic steatosis or hepatic insulin resistance and hepatocellular P i or ATP levels (32). Accordingly, compromised hepatic P i or ATP homeostasis is a possible link between NAFLD and hyperuricemia.…”

mentioning

confidence: 99%

“…1). However, whether dietary fructose contributes to hyperuricemia in liver disease remains debated (1,33,40).…”

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confidence: 99%

“…Lifestyle factors linked to hyperuricemia include obesity and consumption of fructose or ethanol (1,39,43). Of these, fructose has been the most extensively studied from systemic or hepatic vein urate levels in humans after administration of fructose (15,22,23) and from dynamic changes in hepatic ATP and inorganic phosphate (P i ) concentration in human and animal models (21,22,34).…”

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The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis

Petrie

Patman

Sinha

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Petrie JL, Patman GL, Sinha I, Alexander TD, Reeves HL, Agius L. The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis. Am J Physiol Endocrinol Metab 305: E1255-E1265, 2013. First published September 17, 2013; doi:10.1152/ajpendo.00214.2013.-Plasma levels of uric acid, the final product of purine degradation in humans, are elevated in metabolic syndrome and are strongly associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD). Hepatic and blood levels of purine metabolites (inosine, hypoxanthine, and xanthine) are also altered in pathophysiological states. We optimized a rat hepatocyte model to test the hypothesis that the production of uric acid by hepatocytes is a potential marker of compromised homeostasis of hepatocellular inorganic phosphate (Pi) and/or ATP. The basal rate of uric acid production from endogenous substrates in rat hepatocytes was comparable to that in human liver and was Ͻ10% of the maximum rate with saturating concentrations of purine substrates. It was marginally (ϳ20%) decreased by insulin and increased by glucagon but was stimulated more than twofold by substrates (fructose and glycerol) that lower both cell ATP and Pi, and by inhibitors of mitochondrial respiration (complexes I, III, and V) that lower ATP but raise cell Pi. Clearance of inosine and its degradation to uric acid were also inhibited by cell Pi depletion. Analysis of gene expression in NAFLD biopsies showed an association between mRNA expression of GCKR, the glucokinase regulatory protein that is functionally linked to uric acid production, and mRNA expression of the phosphate transporters encoded by SLC17A1/3. Uric acid production by hepatocytes is a very sensitive index of ATP depletion irrespective of whether cell Pi is lowered or raised. This suggests that raised plasma uric acid may be a marker of compromised hepatic ATP homeostasis. nonalcoholic fatty liver disease; hyperuricemia; fructose; mitochondrial function PLASMA LEVELS OF URIC ACID, the final product of purine degradation in humans (Fig. 1), are strongly associated with insulin resistance (39) and with nonalcoholic fatty liver disease (NAFLD) (2,20,28). Plasma uric acid reflects the balance between endogenous production by the liver and excretion by the kidney and gut (29). Genome meta-analyses identified common variants in the GCKR gene, which encodes the inhibitor protein of liver glucokinase (GCK) in association with raised serum uric acid levels (18,19,44), and functional studies confirmed a link between GCKR expression in hepatocytes and uric acid production (UAP) (3, 5). However, the minor GCKR variant that associates with raised uric acid levels and hepatic steatosis is associated with decreased rather than increased insulin resistance (26, 31). This indicates that other factors must contribute to the association of hyperuricemia and insulin resistance (39).Lifestyle factors linked to hyperuricemia include obesity and consumption of fructose or ethanol (1, 39, 43). Of these, fr...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…1). However, whether dietary fructose contributes to hyperuricemia in liver disease remains debated (1,33,40).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis

Petrie

Patman

Sinha

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…All these mechanisms initially triggered by the transport of fructose into the hepatocyte are extremely relevant and contribute to the development of diseases such as hyperglycaemia, gout, endothelial inflammation and arterial hypertension [2,31].…”

Section: Sweet Poisonmentioning

confidence: 99%

Fructose Consumption in the Development of Obesity and the Effects of Different Protocols of Physical Exercise on the Hepatic Metabolism

Pereira

Botezelli

Rodrigues

et al. 2017

Preprint

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Fructose consumption has been growing exponentially and, concomitant with this, the increase in the incidence of obesity and associated complications has followed the same behavior.Studies indicate that fructose may be a carbohydrate with greater obesogenic potential than other sugars. In this context, the liver seems to be a key organ for understanding the deleterious health effects promoted by fructose consumption. Fructose promotes complications in glucose metabolism, accumulation of triacylglycerol in the hepatocytes and alterations in the lipid profile, which, associated with an inflammatory response and alterations in the redox state, will imply a systemic picture of insulin resistance. However, physical exercise has been indicated for the treatment of several chronic diseases. In this review, we show how each exercise protocol (aerobic, strength or a combination of both) promote improvements in the obesogenic state created by fructose consumption as an improvement in the serum and liver lipid profile (HDL increase and decrease TG and LDL levels) and a reduction of markers of inflammation caused by an excess of fructose. Therefore, it is concluded that the practice of aerobic physical exercise, strength or a combination of both is essential for attenuating the complications developed by the consumption of fructose.Keywords: fructose; obesity; liver, aerobic exercise, strength exercise, combined exercise. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 28 February 2017doi:10.20944/preprints201702.0103.v1Peer-reviewed version available at Nutrients 2017, 9, , 405; doi:10.3390/nu90404052 of 20 New story/old enemyThe high consumption of sugary beverages rich in fructose, is directly related to the development of obesity and its consequences, such as metabolic syndrome [1][2][3]. Concomitant with the increased incidence and prevalence of obesity and metabolic syndrome, the consumption of fructose has increased around 30% in the last 40 years [4]. More specifically, because fructose is less able to promote satiety and is more palatable, it will stimulate a higher consumption of food [4], and alter the metabolism of lipids and carbohydrates, thereby favouring the synthesis and accumulation of fat [5]. The accumulation of adipose tissue has come to be considered a global public health problem. The hypertrophy of this tissue generates harmful effects on the organism through the secretion of various types of adipokines, and for this reason obesity happens to be considered one of the major risk factors for the development of metabolic syndrome and, consequently, is listed as one of the most serious problems in relation to quality of life [6]. According to epidemiological data, it is expected that by 2025, approximately 18% of men and 21% of women worldwide will be considered obese [7]. With that in mind, since fructose consumption is strongly associated with the development of obesity, studies aimed at evaluating its role in the development of obesity are of paramount importance for a better und...

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Malnutrition and Liver Disease

McClain

Kirpich

Smart

2017

Schiff's Diseases of the Liver

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Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes

Cited by 159 publications

References 39 publications

The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis

The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis

Fructose Consumption in the Development of Obesity and the Effects of Different Protocols of Physical Exercise on the Hepatic Metabolism

Malnutrition and Liver Disease

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