The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis

Herman, Mark A.; Samuel, Varman T.

doi:10.1016/j.tem.2016.06.005

Cited by 190 publications

(160 citation statements)

References 102 publications

Supporting

Mentioning

150

Contrasting

Unclassified

Order By: Relevance

“…Choi et al (82) further showed that the initial oxidative stress in the mitochondria is due to NADPH oxidase, but later there is stimulation of mitochondrial oxidative stress via the electron transport chain, and that these lead to endoplasmic reticulum (ER) stress, the activation of SREBP-1c, and further stimulation of lipogenesis via activation of acetyl CoA carboxylase-1 and FAS (83). Others have also shown fructose-induced induction of the transcription factor, SREBP-1c (83, 108–110) as well as the carbohydrate Responsive-Element Binding Protein (ChREBP) (33, 111). The stimulation of ChREBP results in the stimulation of glucose-6-phosphatase that may mediate some of the gluconeogenic effects of fructose (112).…”

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

722

490

View full text Add to dashboard Cite

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.

show abstract

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

722

490

View full text Add to dashboard Cite

show abstract

“…In addition to providing substrate for lipogenesis, chronic fructose consumption increases transcriptional regulation of DNL by activating key transcription factors, including sterol regulatory element-binding protein 1c (SREBP1c) and carbohydrateresponsive element-binding protein (ChREBP) (122). SREBP1c promotes lipid synthesis and is regulated at the transcriptional and posttranslational levels by nutrients and hormones.…”

Section: Genetic Lessons About Fructose Metabolismmentioning

confidence: 99%

Fructose metabolism and metabolic disease

Hannou

Haslam

McKeown

et al. 2018

Journal of Clinical Investigation

Self Cite

418

356

View full text Add to dashboard Cite

“…ChREBP KO mice are intolerant to fructose and have reduced hepatic triglyceride levels and hepatic DNL rates on high-starch diets [13]. Thus, fructose may contribute to hepatic steatosis through at least two mechanisms: 1) by providing substrate for fatty-acid synthesis and esterification in the liver and 2) by stimulating hepatic lipogenic gene programs under the control of ChREBP and other signaling factors [reviewed in [14]]. …”

Section: Introductionmentioning

confidence: 99%

A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism

Fisher

Kim

Doridot

et al. 2017

Molecular Metabolism

Self Cite

139

124

View full text Add to dashboard Cite

ObjectiveIncreased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption.MethodsWe tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects.ResultsHepatic expression of ChREBP-β and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-β and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls.ConclusionsIn summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.

show abstract

The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis

Cited by 190 publications

References 102 publications

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

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

Fructose metabolism and metabolic disease

A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism

Contact Info

Product

Resources

About