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

Abstract

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.

Childhood Fructoholism and Fructoholic Liver Disease

“…Fructose is the major constituent of common sweeteners, such as sucrose (table sugar), high fructose corn syrup, and agave syrup, which consist of a mixture of fructose and glucose monosaccharides . Fructose consumption has risen uncontrollably over the past century, especially by ingestion of sugar‐sweetened beverages .…”

“…Fructose is the major constituent of common sweeteners, such as sucrose (table sugar), high fructose corn syrup, and agave syrup, which consist of a mixture of fructose and glucose monosaccharides . Fructose consumption has risen uncontrollably over the past century, especially by ingestion of sugar‐sweetened beverages . It can also be found in fruits and honey, although with less noxious outcome than fructose in added sugar compounds due to its lower concentration and the presence of other constituents (primarily antioxidants and fibers) that alter its metabolic effect .…”

“…This transient decrease of adenosine triphosphate does not occur with glucose metabolization and is the key to fructose‐mediated negative metabolic effects. One of those effects is intrahepatic lipid accumulation (steatosis) due to an increase in hepatic fatty acid (FA) synthesis from de novo lipogenesis (DNL), an increase in hepatic delivery of FAs, and a decrease in lipid clearance . Dietary sugars have been shown to enhance hepatic DNL, a metabolic pathway that affects lipid and glucose regulation and induces insulin resistance, cardiovascular disease, and hepatic steatosis .…”

“…Fructose intake has a dose‐dependent correlation with NAFLD development and its progression to fibrosis in children and adolescents . A study including 271 obese adolescents with biopsy‐proven NAFLD showed that fructose consumption was significantly higher in patients with NASH compared with NAFLD, and patients from the first group had significantly higher uric acid levels .…”

“…(29) Moreover, taking into account the ongoing rise of fructose consumption and childhood obesity and its role in NAFLD, a significative number of children might need liver transplantation and at earlier ages if no effective measures are assumed. (30,31) NASH recurrence in allograft with requirement of retransplantation is well recognized and can occur within a few months after transplantation if no solid lifestyle modification is attempted. (19,20,32,33) In adults, NAFDL is clearly associated with HCC even without the presence of significant fibrosis.…”