Review Article: Fructose in Non-alcoholic Fatty Liver Disease
Authors and Disclosures
Posted: 05/15/2012; Alimentary Pharmacology & Therapeutics. 2012;35(10):1135-1144. © 2012 Blackwell Publishing
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Abstract and Introduction
Linking Fructose to NAFLD: Indirect Mechanisms
Linking Fructose to NAFLD: Direct Mechanisms
Open Issues and Conclusions
Abstract and Introduction
Background The role of excess fructose intake in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has recently received increasing attention, but the pathophysiology of this relationship has been only partly elucidated.
Aim To provide an overview of the potential role played by fructose in the pathogenesis of NAFLD by focusing on both indirect and direct harmful effects.
Methods Experimental and clinical studies which investigated the relation of fructose with NAFLD are reviewed.
Results Several factors may potentially contribute to fructose-induced NAFLD, including the induction of the metabolic syndrome, copper deficiency, bacterial translocation from the gut to the liver, the formation of advanced glycation endproducts and a direct dysmetabolic effect on liver enzymes.
Conclusions Experimentally-increased fructose intake recapitulates many of the pathophysiological characteristics of the metabolic syndrome in humans, which may in turn lead to NAFLD. However, the majority of experimental studies tend to involve feeding excessively high levels of fructose (60–70% of total energy intake) which is not reflective of average human intake. Hopefully, the combination of in vivo, in vitro and genetic research will provide substantial mechanistic evidence into the role of fructose in NAFLD development and its complications.
Non-alcoholic fatty liver disease (NAFLD) is a common but often silent chronic liver disease characterised by the accumulation of triglycerides in hepatocytes occurring in people who consume little or no alcohol.[1–3] This condition comprises a wide spectrum of histological lesions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), a parenchymal liver inflammation which can develop further to fibrosis, cirrhosis and hepatocellular carcinoma.[4,5] NAFLD is strongly associated with obesity and insulin resistance and is currently conceptualised as the hepatic manifestation of metabolic syndrome (MS).[6–8] Growing evidence suggests that the fast-growing and alarming epidemic of NAFLD is closely intertwined with the Westernisation of dietary patterns with an increasing intake of simple sugars, especially fructose.[9–14]
Fructose is an isomer of glucose with a hydroxyl group on carbon-4 reversed in position. Recent decades have witnessed an enormous rise in fructose consumption. Studies on ancestral diets have shown that 8000–10 000 years ago the average intake of fructose per capita was around 2 kg per year. Significant increases observed after the abolition of sugar tax in the 1870’s saw fructose consumption increase to 45 kg by 1950. Notably, by 1997 consumption had risen consistently to 69 kg per annum.[13,16] Currently, fructose is massively used in the food industry due to its sweeter taste and its lack of inhibition of satiety compared with other sugars. From a metabolic standpoint, fructose is absorbed by the small intestine and is transported across the epithelial barrier into cells and the bloodstream by the fructose-specific GLUT5 transporter. Entry of fructose into cells is not insulin-dependent and does not promote insulin secretion unlike glucose. Absorbed fructose is transported in plasma via the hepatic portal vein to the liver where fructose is predominantly metabolised via its phosphorylation; only a small amount of fructose is metabolised by hexokinase in muscle and adipose tissue.[13,16] Further metabolism of fructose produces 3-carbon intermediates in the glycolytic pathway that are identical to those derived from glucose.
Starting from the 1960s, a number of animal and human studies have reported associations with excessive fructose consumption and adverse metabolic effects, which may have important hepatic consequences (including the development of NAFLD). The potential role of fructose in the pathogenesis of NAFLD has thus recently gained mounting attention and has been previously reviewed in detail.[9–17] However, the extent to which fructose consumption is playing a role in liver damage and failure has not yet been investigated fully. Theoretically, fructose consumption can be linked to NAFLD via two main pathophysiological mechanisms: the first can be defined as ‘indirect’ (i.e. fructose can lead to prominent metabolic adverse effects which can in turn increase the risk of developing NAFLD), whereas the second one is more ‘direct’ and could involve a direct hepatotoxic damage (Figure 1).
Potential direct and indirect mechanisms by which fructose may predispose to NAFLD.
This article provides an overview of the potential role played by fructose in the pathogenesis of NAFLD by focusing on both indirect and direct harmful effects. The list of pathophysiological mechanisms provided in this review is not intended to be exhaustive; rather, a brief summary of some key links between fructose and NAFLD is provided.