Abstract
Non-alcoholic fatty liver disease (NAFLD) represents the result of hepatic fat overload not due to alcohol consumption and potentially evolving to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Fructose is a naturally occurring simple sugar widely used in food industry linked to glucose to form sucrose, largely contained in hypercaloric food and beverages. An increasing amount of evidence in scientific literature highlighted a detrimental effect of dietary fructose consumption on metabolic disorders such as insulin resistance, obesity, hepatic steatosis, and NAFLD-related fibrosis as well. An excessive fructose consumption has been associated with NAFLD development and progression to more clinically severe phenotypes by exerting various toxic effects, including increased fatty acid production, oxidative stress, and worsening insulin resistance. Furthermore, some studies in this context demonstrated even a crucial role in liver cancer progression. Despite this compelling evidence, the molecular mechanisms by which fructose elicits those effects on liver metabolism remain unclear. Emerging data suggest that dietary fructose may directly alter the expression of genes involved in lipid metabolism, including those that increase hepatic fat accumulation or reduce hepatic fat removal. This review aimed to summarize the current understanding of fructose metabolism on NAFLD pathogenesis and progression.
Highlights
In a short-term interventional study, the metabolic effects of SSBs contained in high-fructose corn syrup were determined on 85 volunteers showing a dose-dependent increase of lipid/lipoproteins and uric acid, which occurred within 2 weeks of administration, and even fructose was in the “range” of normal consumption [11]
endoplasmic reticulum (ER) stress promotes the initiation of inflammatory and apoptotic pathways through c-Jun N-terminal kinase (JNK), nuclear factor kB (NFkB), and CCAAT/enhancer-binding homologous protein (CHOP), which play an important role in nonalcoholic fatty liver disease (NAFLD) progression [69,75]
GLUT 5 transporter present in the blood–brain barrier allows fructose to enter in the central nervous system, triggering the phosphorylation of the energy sensor of AMP-activated protein kinase in neurons of the paraventricular nucleus of the hypothalamus; the fructose may induce the release of corticotropin-releasing hormone (CRH) and, subsequently, of adrenocorticotropic hormone (ACTH), stimulating the corticosteroids production [84]
Summary
Fructose is responsible for the activation of several pathways involved in lipogenesis, gluconeogenesis, and glycolysis, irrespective of negative feedback regulations link to insulin signaling (Figure 2) [42]. SREBP1c and ChREBP are potent inducers of lipogenesis by mean of triggering the activation of genes such as fatty acid synthase (FAS) and acetyl coA carboxylase (ACC) [38] In this way, fructose acts as the substrate and the activator of DNL, representing a potent lipogenic carbohydrate that contributes to the development of liver steatosis. Some studies on murine models demonstrated that high-fructose diet is able to induce a reduction in the phosphorylation of insulin receptors substrate (IRS)-1 and the expression of IRS2 and FoxO1, resulting in the inhibition of insulin signaling and the increase of plasma glucose excursions during glucose and pyruvate tolerance tests [60,61]. Despite the amount of evidence regarding direct and indirect effects of fructose on insulin signaling, strong scientific evidence derived from well-constructed clinical studies is still required
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