Abstract
Glucose is a major energy source for the entire body, while fructose metabolism occurs mainly in the liver. Fructose consumption has increased over the last decade globally and is suspected to contribute to the increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is a manifestation of metabolic syndrome affecting about one-third of the population worldwide and has progressive pathological potential for liver cirrhosis and cancer through non-alcoholic steatohepatitis (NASH). Here we have reviewed the possible contribution of fructose to the pathophysiology of NAFLD. We critically summarize the current findings about several regulators, and their potential mechanisms, that have been studied in humans and animal models in response to fructose exposure. A novel hypothesis on fructose-dependent perturbation of liver regeneration and metabolism is advanced. Fructose intake could affect inflammatory and metabolic processes, liver function, gut microbiota, and portal endotoxin influx. The role of the brain in controlling fructose ingestion and the subsequent development of NAFLD is highlighted. Although the importance for fructose (over)consumption for NAFLD in humans is still debated and comprehensive intervention studies are invited, understanding of how fructose intake can favor these pathological processes is crucial for the development of appropriate noninvasive diagnostic and therapeutic approaches to detect and treat these metabolic effects. Still, lifestyle modification, to lessen the consumption of fructose-containing products, and physical exercise are major measures against NAFLD. Finally, promising drugs against fructose-induced insulin resistance and hepatic dysfunction that are emerging from studies in rodents are reviewed, but need further validation in human patients.
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Abbreviations
- CYP2E1:
-
Cytochrome 450 2E1
- ER:
-
Endoplasmic reticulum
- GLUT:
-
Glucose transporter
- HDL:
-
High-density lipoprotein
- HFCS:
-
High-fructose corn syrup
- HFD:
-
High-fat diet
- IR:
-
Insulin resistance
- IRS-1/2:
-
Insulin receptor substrate 1/2
- LCN2:
-
Lipocalin 2
- LDL:
-
High-density lipoprotein
- LPS:
-
Lipopolysaccharide
- Ltf:
-
Lactoferrin
- MC4R:
-
Melanocortin receptor 4
- MetS:
-
Metabolic syndrome
- NAFLD:
-
Non-alcoholic fatty liver disease
- NASH:
-
Non-alcoholic steatohepatitis
- PAI-1:
-
Plasminogen activator inhibitor-1
- ROS:
-
Reactive oxygen species
- T2D:
-
Type 2 diabetes mellitus
- TG:
-
Triglycerides
- TLR4:
-
Toll-like receptor 4
- TNF-α:
-
Tumor necrosis factor-α
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Acknowledgements
S.M.A. and R.G. conceived, designed, wrote, and approved the final manuscript. The authors thank Dr. John Hallett, MCR Centre for Regenerative Medicine, The University of Edinburgh, UK, for proofreading the paper.
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This study was supported by grants from the Bundesministerium für Forschung und Technologie (BMBF) in the framework of the Systems Biology initiative “Virtual Liver Network” to RG (Grant: 0315735).
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Alwahsh, S.M., Gebhardt, R. Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD). Arch Toxicol 91, 1545–1563 (2017). https://doi.org/10.1007/s00204-016-1892-7
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DOI: https://doi.org/10.1007/s00204-016-1892-7