Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling

Softic, Samir; Gupta, Manoj; Wang, Guo-Xiao; Fujisaka, Shiho; O’Neill, Brian T.; Rao, Tata Nageswara; Willoughby, Jennifer L. S.; Harbison, Carole; Fitzgerald, Kevin T.; Newgard, Christopher B.; Cohen, David E.; Kahn, C. Ronald

doi:10.1172/jci99009

Cited by 88 publications

(123 citation statements)

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“…C,D). Further, genetic ablation of NOX2 did not modulate the expression of mediators central for insulin‐induced glucose homeostasis in liver and eWAT (e.g., glucose transporter 1 [ Glut1 ], Glut4 , carbohydrate‐responsive element‐binding protein β, and sterol regulatory element binding protein 1c; data not shown) . Overall, these data suggest that NOX2 regulates glucose but not insulin metabolism in HFD‐induced obesity.…”

Section: Resultssupporting

confidence: 92%

Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice

Mukherjee

Moreno‐Fernandez

Giles

et al. 2018

Hepatology Communications

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Nonalcoholic fatty liver disease (NAFLD) represents a disease spectrum ranging from benign steatosis to life‐threatening cirrhosis and hepatocellular carcinoma. Elevated levels of reactive oxygen species (ROS) and exacerbated inflammatory responses have been implicated in NAFLD progression. Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 (NOX2; also known as gp91Phox), the main catalytic subunit of the nicotinamide adenine dinucleotide phosphate (reduced) oxidase complex, modulates ROS production, immune responsiveness, and pathogenesis of obesity‐associated metabolic derangements. However, the role of NOX2 in the regulation of immune cell function and inflammatory vigor in NAFLD remains underdefined. Here, we demonstrate that obesogenic diet feeding promoted ROS production by bone marrow, white adipose tissue, and liver immune cells. Genetic ablation of NOX2 impeded immune cell ROS synthesis and was sufficient to uncouple obesity from glucose dysmetabolism and NAFLD pathogenesis. Protection from hepatocellular damage in NOX2‐deficient mice correlated with reduced hepatic neutrophil, macrophage, and T‐cell infiltration, diminished production of key NAFLD‐driving proinflammatory cytokines, and an inherent reduction in T‐cell polarization toward Th17 phenotype. Conclusion: Current findings demonstrate a crucial role of the NOX2–ROS axis in immune cell effector function and polarization and consequent NAFLD progression in obesity. Pharmacologic targeting of NOX2 function in immune cells may represent a viable approach for reducing morbidity of obesity‐associated NAFLD pathogenesis. (Hepatology Communications 2018;2:546‐560)

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Section: Resultssupporting

confidence: 92%

Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice

Mukherjee

Moreno‐Fernandez

Giles

et al. 2018

Hepatology Communications

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“…Indeed, also maltodextrin exaggerates the effects of a high‐fat diet (Mei et al, ). With similar caloric intake, fructose administered via the drinking water gives worse metabolic outcomes than glucose administered via the drinking water in animals on a high‐fat diet (Softic et al, ). The overall macronutrient intake was also shifted to some extend in that study (Softic et al, ).…”

Section: Discussionmentioning

confidence: 99%

Metabolic effects of the dietary monosaccharides fructose, fructose–glucose, or glucose in mice fed a starch‐containing moderate high–fat diet

et al. 2020

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Fructose consumption has been linked to obesity and increased hepatic de novo lipogenesis (DNL). Excessive caloric intake often confounds the results of fructose studies, and experimental diets are generally low‐fat diets, not representative for westernized diets. Here, we compared the effects of dietary fructose with those of dietary glucose, in adult male and female mice on a starch‐containing moderate high–fat (HF) diet. After 5 weeks fattening on a HF high‐glucose (HF‐G) diet, mice were stratified per sex and assigned to one of the three intervention diets for 6 weeks: HF high fructose (HF‐F), HF with equimolar glucose and fructose (HF‐GF), or HF‐G. Bodyweight (BW) and food intake were measured weekly. Indirect calorimetry was performed on week 5; animals were sacrificed in food‐deprived state on week 6. Data were analyzed within sex. BW gain was similar among animals on the HF‐G, HF‐GF, and HF‐F diets. Cumulative food intake was slightly lower in HF‐F animals (both sexes). However, energy expenditure was not affected, or were circulating insulin and glucose concentrations, and hepatic triglyceride levels at endpoint. Hepatic gene expression analysis showed only minor alterations in hexokinase and glycolysis‐related expression in males, and no alterations in sugar transporters, or DNL‐related enzymes. In females, no consistent alterations in hepatic or small intestine gene expression were seen. Concluding, partial or complete replacement of dietary glucose with fructose does not increase caloric intake, and does not affect BW, hepatic triglyceride levels, or insulin concentrations in male and female mice on a moderate high–fat diet.

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“…In addition, another study by Softic, et al . (85) found fructose, but not glucose drove lipogenic enzymes, and insulin resistance through fructokinase, and that fructokinase levels are elevated in fructose fed mice as well as obese humans with NASH (86). Thus, these studies suggest that there is a unique property of the fructokinase C pathway that leads to hepatic steatosis, and raises the possibility that it may relate to the transient ATP depletion, intracellular phosphate depletion or uric acid generation (16).…”

Section: Fructokinase the Principal Enzyme Driving Fructose-inducedmentioning

confidence: 99%

Fructose and sugar: A major mediator of non-alcoholic fatty liver disease

Jensen

Abdelmalek

Sullivan

et al. 2018

Journal of Hepatology

692

490

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Nonalcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result from overnutrition and sedentary lifestyle, recent evidence suggests that diets high in sugar (from sucrose and/or high fructose corn syrup (HFCS)) not only increases the risk for NAFLD, but also, nonalcoholic steatohepatitis (NASH). Here we review the experimental and clinical evidence that fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked with metabolism of fructose by fructokinase C, resulting in ATP consumption, nucleotide turnover and uric acid generation that mediate fat accumulation. Alterations in gut permeability, microbiome, and associated endotoxemia contributes to the risk of NAFLD and NASH. Early clinical studies suggest that reducing sugary beverages and total fructose intake, especially from added sugars, may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease.

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Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling

Cited by 88 publications

References 0 publications

Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice

Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice

Metabolic effects of the dietary monosaccharides fructose, fructose–glucose, or glucose in mice fed a starch‐containing moderate high–fat diet

Fructose and sugar: A major mediator of non-alcoholic fatty liver disease

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