Liquid fructose down-regulates liver insulin receptor substrate 2 and gluconeogenic enzymes by modifying nutrient sensing factors in rats

Rebollo, Alba; Roglans, Núria; Baena, Miguel; Padrosa, Anna; Sánchez, Rosa María Galán; Alegret, Marta; Laguna, Juan C.

doi:10.1016/j.jnutbio.2013.10.014

Cited by 35 publications

(22 citation statements)

References 48 publications

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“…Several studies indicate that exposure of liver cells to high glucose, fructose or sucrose content induce hepatic insulin resistance in rodent 99,100 which can be the consequence of decreased insulin receptor expression or increased phosphorylation of the insulin receptor substrate (IRS)1 therefore suppressing insulin receptor signaling 101,102 . The deleterious effects of chronic hyperglycemia on insulin sensitivity have been linked, among others, to oxidative stress, inflammation and ER stress 103 .…”

Section: ) Harmful Effects Of Hepatotoxic Carbohydratesmentioning

confidence: 99%

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

et al. 2016

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The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.

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Section: ) Harmful Effects Of Hepatotoxic Carbohydratesmentioning

confidence: 99%

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

et al. 2016

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“…Thus, although caution is needed when extending results of animal studies to humans, rats are useful models to understand the molecular mechanisms underlying the metabolic derangements caused by high-fructose diets. We have previously shown that the administration of a 10% w/v fructose solution to female rats caused hyperinsulinaemia, glucose intolerance, reduced insulin receptor substrate-2 (IRS-2) hepatic expression, and hepatic steatosis, which we attributed to the induction of carbohydrate response element binding protein (ChREBP) 10 11 . In these studies, fructose was administered for 14 days, which is a short treatment period given that fructose consumption patterns in humans extend over many years.…”

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confidence: 95%

Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues

Baena

Sangüesa

Dávalos

et al. 2016

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Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months’ supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake.

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“…Our research group has shown that liquid fructose supplementation in female rats fed a standard chow diet (two weeks to two months) induces glucose intolerance and IR [12,13,14,15]. However, unhealthy human dietary patterns frequently include not only excessive added sugars, but also excessive fat intake, particularly saturated fats [16].…”

Section: Introductionmentioning

confidence: 99%

The Addition of Liquid Fructose to a Western-Type Diet in LDL-R−/− Mice Induces Liver Inflammation and Fibrogenesis Markers without Disrupting Insulin Receptor Signalling after an Insulin Challenge

et al. 2017

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A high consumption of fat and simple sugars, especially fructose, has been related to the development of insulin resistance, but the mechanisms involved in the effects of these nutrients are not fully understood. This study investigates the effects of a Western-type diet and liquid fructose supplementation, alone and combined, on insulin signalling and inflammation in low-density lipoprotein (LDL) receptor-deficient mice (LDL-R−/−). LDL-R−/− mice were fed chow or Western diet ±15% fructose solution for 12 weeks. Plasma glucose and insulin, and the expression of genes related to inflammation in the liver and visceral white adipose tissue (vWAT), were analysed. V-akt murine thymoma viral oncogene homolog-2 (Akt) activation was measured in the liver of the mice after a single injection of saline or insulin. None of the dietary interventions caused inflammation in vWAT, whereas the Western diet induced hepatic inflammation, which was further enhanced by liquid fructose, leading also to a significant increase in fibrogenesis markers. However, there was no change in plasma glucose or insulin, or insulin-induced Akt phosphorylation. In conclusion, hepatic inflammation and fibrogenesis markers induced by a Western diet supplemented with liquid fructose in LDL-R−/− mice are not associated with a significant impairment of hepatic insulin signalling.

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Liquid fructose down-regulates liver insulin receptor substrate 2 and gluconeogenic enzymes by modifying nutrient sensing factors in rats

Cited by 35 publications

References 48 publications

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues

The Addition of Liquid Fructose to a Western-Type Diet in LDL-R−/− Mice Induces Liver Inflammation and Fibrogenesis Markers without Disrupting Insulin Receptor Signalling after an Insulin Challenge

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