Fructose-mediated stress signaling in the liver: implications for hepatic insulin resistance.

Organisms reprogram metabolic pathways to adapt to changes in nutrient availability. This requires that nutrient-based stimuli are sensed, signals are transmitted, and highly specific responses are engaged. We propose that in the liver, the mitogen-activated protein kinase, c-jun N-terminal kinase (JNK), links excessive nutrient metabolism with impaired insulin regulation of glucose production. The liver, by virtue of its anatomic position and selective regulatory features, buffers and is highly responsive to changes in nutrient delivery. In particular, sugars such as sucrose and fructose uniquely regulate and are selectively metabolized by the liver. We propose that when hepatic fructose uptake exceeds requirements for glycogen and energy (hepatic sugar excess), the JNK-signaling pathway is engaged as part of the adaptive response.

Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells.

Accumulation of lipids in nonadipose tissues can lead to cell dysfunction and cell death, a phenomenon known as lipotoxicity. However, the signaling pathways and mechanisms linking lipid accumulation to cell death are poorly understood. The present study examined the hypothesis that saturated fatty acids disrupt endoplasmic reticulum (ER) homeostasis and promote apoptosis in liver cells via accumulation of ceramide. H4IIE liver cells were exposed to varying concentrations of saturated (palmitate or stearate) or unsaturated (oleate or linoleate) fatty acids. ER homeostasis was monitored using markers of the ER stress response pathway, including phosphorylation of IRE1alpha and eIF2alpha, splicing of XBP1 mRNA, and expression of molecular chaperone (e.g., GRP78) and proapoptotic (CCAAT/enhancer-binding protein homologous protein) genes. Apoptosis was monitored using caspase activity and DNA laddering. Palmitate and stearate induced ER stress, caspase activity, and DNA laddering. Inhibition of caspase activation prevented DNA laddering. Unsaturated fatty acids did not induce ER stress or apoptosis. Saturated fatty acids increased ceramide concentration; however, inhibition of de novo ceramide synthesis did not prevent saturated fatty acid-induced ER stress and apoptosis. Unsaturated fatty acids rescued palmitate-induced ER stress and apoptosis. These data demonstrate that saturated fatty acids disrupt ER homeostasis and induce apoptosis in liver cells via mechanisms that do not involve ceramide accumulation.

Immediate-early gene induction in hippocampus and cortex as a result of novel experience is not directly related to the stressfulness of that experience.

The stressful quality of an experience, as perceived by rats, is believed to be largely represented by the magnitude of a hypothalamic-pituitary-adrenal (HPA) axis response. The hippocampus may be especially important for assessing the stressfulness of psychological stressors such as novel experience. If such is the case then experience-dependent immediate-early gene expression levels within the hippocampus may parallel relative levels of HPA axis activity. We examined this prospect in rats that were placed in four different novel environments (empty housing tub, circular arena, elevated pedestal or restraint tube). Restraint and pedestal produced the largest magnitude of increased ACTH and corticosterone secretion, arena an intermediate level (Experiment 2) and tub the least magnitude of increase. We saw a very similar experience-dependent pattern of relative Fos protein, c-fos mRNA and zif268 mRNA expression in the paraventricular nucleus of the hypothalamus. However, in hippocampus (and select regions of cortex), immediate-early gene expression was associated with the exploratory potential of the novel experience rather than level of HPA axis activity; pedestal and arena elicited the greatest immediate-early gene expression, tub an intermediate level and restraint the least amount of expression. We conclude that the stressfulness of psychological stressors is not represented by the amount of immediate-early gene induction elicited in hippocampus and cortex, nor does there appear to be a general enhancing or depressive influence of acute stress on immediate-early gene induction in those brain regions.