Fructose-associated hepatotoxicity indexed by the lactate dehydrogenase isoenzyme LDH-5.

Modern diets have become increasingly rich in fructose, for example through the addition of high-fructose corn syrup to many foods and drinks. It has been suggested that this might lead to hepatotoxicity, including the development of non-alcoholic fatty liver disease. After entering hepatocytes via insulin-independent glucose transporter 2 transmembrane carrier proteins, fructose is phosphorylated to fructose-1-phosphate in a reaction catalysed by fructokinase (ketohexokinase). In turn, fructose-1-phosphate is hydrolysed by aldolase B to glyceraldehydes. Glyceraldehydes may enter gluconeogenesis via fructose-1,6-bisphosphate and fructose-6-phosphate; glyceraldehydes may also enter glycogenolysis via pyruvate. The last pathway involves conversion of pyruvate to acetyl-CoA. Alternatively, pyruvate may be converted, via the action of the hepatic lactate dehydrogenase isoenzyme LDH-5, into lactate. In liver damage, the LDH-5 isoenzyme becomes elevated, predominantly in serum/plasma. We therefore hypothesised that if dietary fructose is associated with hepatotoxicity, there should be a positive correlation between erythrocyte fructose-6-phosphate and plasma LDH-5. This hypothesis was tested by assaying venous blood samples taken from 39 patients at rest, three hours after eating. Quantitative Fourier transform infrared spectrometry following gel electrophoresis was used to assay erythrocyte fructose-6-phosphate levels. Similarly, plasma LDH-5 concentrations were spectrophotometrically analysed, using the pyruvate-lactate reaction, following electrophoretic separation of the LDH isoenzymes. A significant positive correlation was found between the two variables (r = 0.44, p = 0.0047). This result, which supports our hypothesis, is evidence in favour of the possibility that dietary fructose is associated with hepatotoxicity. In addition to being a marker of hepatic damage, LDH-5 may play a more direct epigenetic role in causing liver damage; acute hepatic injury is associated with nuclear translocation of LDH, causing the production of lactate from pyruvate in the nucleus; in turn, the lactate inhibits histone deacetylase and is associated with upregulation of genes associated with the damage response, leading to cell death.

Inverse relationship between human erythrocyte fructose-6-phosphate and short-chain fatty acid levels.

In muscle cells, fructose is initially metabolised to fructose-6-phosphate. In the liver, fructose is metabolised to fructose-1-phosphate and thence to glyceraldehydes, which in turn can either enter glycogenolysis via pyruvate or gluconeogenesis via fructose-1,6-bisphosphate and fructose-6-phosphate. High levels of fructose-1-phosphate inhibit both glycogenolysis and gluconeogenesis. We hypothesised that, if systemically absorbed short-chain fatty acids constitute a major metabolic fate of unabsorbed dietary fructose, then levels of erythrocyte fructose-6-phosphate would be inversely correlated with plasma levels of short-chain fatty acids. The aim of this study was to test this hypothesis in respect of the three main short-chain fatty acids acetate, propionate and butyrate. Venous blood samples from 39 patients (16 male, 23 female, mean (standard error) age 42.4 (3.3) years) were analysed. Erythrocyte fructose-6-phosphate was measured using quantitative Fourier transform infrared spectrometry following gel electrophoresis, while plasma acetate, propionate and butyrate levels were measured using gas-liquid chromatography. The erythrocyte fructose-6-phosphate level was inversely correlated with the plasma acetate (r = -0.30, p = 0.06), propionate (r = -0.31, p = 0.05) and butyrate (r = -0.40, p = 0.01). These results support our hypothesis. The conversion of unabsorbed dietary fructose into short-chain fatty acids may represent a protective mechanism against the adverse effects of hypoglycaemia.