Fructose‐induced stress signaling in hepatocytes involves methylglyoxal

Abstract

Fructose produces hepatic insulin resistance in humans and animals. We have proposed that the selective metabolism of fructose by the liver and the unique ability of fructose‐1‐phosphate to stimulate hepatic glucose uptake can, under conditions of elevated fructose delivery, inflict a metabolic insult that is localized to the hepatocyte. The present study was designed to identify potential cellular effectors of this insult. Primary hepatocytes were incubated with 8 mM glucose and 0.12% inulin (G, n=6) or 8 mM glucose, 0.12% inulin, and 28 mU of inulinase (GF, n=6) in the presence or absence of insulin for 0, 2, or 4h. GF produced fructose concentrations of ~0.7 mM over the 4h experiment. GF induced phosphorylation of MKK7 and JNK, phosphorylation of serine307 on IRS‐1, and reduced tyrosine phosphorylation of IRS‐1 and ‐2. GF increased ceramide levels and reactive oxygen species (ROS); however inhibitors of ceramide synthesis or ROS accumulation did not prevent GF‐mediated changes in MKK7, JNK or IRS proteins. Low concentrations of methylglyoxal recapitulated the GF‐induced changes in MKK7, JNK and IRS proteins. We hypothesize that GF‐mediated changes in stress signaling involves methylglyoxal in primary hepatocytes.