Dietary fructose exacerbates hepatocellular injury when incorporated into a methionine-choline-deficient diet

Abstract

Background Methionine-choline-deficient (MCD) diets cause steatohepatitis in rodents and are used to model fatty liver disease in human beings. Recent studies have identified sucrose as a major contributor to MCD-related liver disease through its ability to promote hepatic de novo lipogenesis. Aims To determine whether glucose and fructose, the two constitutents of sucrose, differ in their capacity to provoke steatohepatitis when incorporated individually into MCD formulas. Materials & Methods MCD and control formulas prepared with either glucose or fructose as the sole source of carbohydrate were fed to mice for 21 days. Liver injury was assessed biochemically and histologically together with hepatic gene expression and fatty acid analysis. Results Mice fed MCD formulas developed similar degrees of hepatic steatosis whether they contained glucose or fructose. By contrast, mice fed MCD-fructose developed significantly more hepatocellular injury than mice fed MCD-glucose, judged by histology, apoptosis staining and serum alanine aminotransferase. Liver injury in MCD-fructose mice coincided with an exaggerated rise in the ratio of long-chain saturated to unsaturated fatty acids in the liver. Notably, hepatic inflammation was not enhanced in mice fed MCD-fructose, correlating instead with hepatic lipid peroxidation, which was equivalent in the two MCD groups. Discussion Fructose is more cytotoxic than glucose when used as the source of carbohydrate in MCD formulas. Conclusion The data suggest the enhanced cytotoxicity of fructose in the MCD model is related to its ability to stimulate de novo lipogenesis, which yields harmful long-chain saturated fatty acids.

Isocaloric manipulation of macronutrients within a high-carbohydrate/moderate-fat diet induces unique effects on hepatic lipogenesis, steatosis and liver injury

“…The results of the current experiments mirror those from recent studies involving nutrient manipulation in the MCD model of fatty liver disease [12, 13, 45]. Indeed, in the setting of an MCD diet, pairing sucrose with palmitate induced the worst liver disease of any carbohydrate-fat combination [12, 13, 17, 45].…”

“…Indeed, in the setting of an MCD diet, pairing sucrose with palmitate induced the worst liver disease of any carbohydrate-fat combination [12, 13, 17, 45]. In the current study, sucrose-palmitate caused much milder liver disease than it did in the MCD model; this is likely because the diets contained methionine and choline, and thus eliminated the confounding effect of MCD-related hepatic lipid trapping.…”

“…Specifically, simple sugar must be present in the MCD formula for it to induce steatohepatitis. When sugar is replaced with complex carbohydrate, the ability of the diet to induce liver injury is markedly reduced [12, 13]. …”

New Insights from Rodent Models of Fatty Liver Disease

“…Taken together, these findings suggest that saturated fatty acids derived from de novo lipogenesis are important mediators of hepatocellular death in fatty liver disease. Recent experiments have confirmed this by showing that MCD formulas lacking sugar fail to cause liver disease (91), whereas MCD formulas that incorporate pure fructose, a highly lipogenic substrate, into the MCD formula, enhance its ability to cause hepatocyte death (90) (Fig. 4).…”

“…Our group has recently tested the impact of fructose on liver injury by comparing it directly to glucose as the sole carbohydrate in a methionine-choline-deficient diet (see below). In this setting, fructose stimulates more hepatic lipogenesis than glucose and causes significantly more liver cell death than glucose (90).…”