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

Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid-induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.

Nonalcoholic fatty liver disease is a relatively new hepatic sequela of obesity and type 2 diabetes. The pathogenesis of liver injury and disease progression in nonalcoholic fatty liver disease, however, is poorly understood. The present study examined the hypothesis that the composition of fatty acids in the steatotic liver promotes liver injury. Using dietary models of hepatic steatosis characterized by similar accumulation of total triglyceride but different composition of fatty acids, we show that hepatic steatosis characterized by increased saturated fatty acids is associated with increased liver injury and markers of endoplasmic reticulum stress (e.g. X-box binding protein-1 mRNA splicing and glucose-regulated protein 78 expression). These changes preceded and/or occurred independently of obesity and differences in leptin, TNFalpha, insulin action, and mitochondrial function. In addition, hepatic steatosis characterized by increased saturated fatty acids reduced proliferative capacity in response to partial hepatectomy and increased liver injury in response to lipopolysaccharide. These data suggest that the composition of fatty acids in the steatotic liver is an important determinant of susceptibility to liver injury.

This study aimed to determine gender-based differences in fuel metabolism in response to long-duration exercise. Fuel oxidation and the metabolic response to exercise were compared in men (n = 14) and women (n = 13) during 2 h (40% of maximal O2 uptake) of cycling and 2 h of postexercise recovery. In addition, subjects completed a separate control day on which no exercise was performed. Fuel oxidation was measured using indirect calorimetry, and blood samples were drawn for the determination of circulating substrate and hormone levels. During exercise, women derived proportionally more of the total energy expended from fat oxidation (50.9 +/- 1.8 and 43. 7 +/- 2.1% for women and men, respectively, P < 0.02), whereas men derived proportionally more energy from carbohydrate oxidation (53.1 +/- 2.1 and 45.7 +/- 1.8% for men and women, respectively, P < 0.01). These gender-based differences were not observed before exercise, after exercise, or on the control day. Epinephrine (P < 0.007) and norepinephrine (P < 0.0009) levels were significantly greater during exercise in men than in women (peak epinephrine concentrations: 208 +/- 36 and 121 +/- 15 pg/ml in men and women, respectively; peak norepinephrine concentrations: 924 +/- 125 and 659 +/- 68 pg/ml in men and women, respectively). As circulating glycerol levels were not different between the two groups, this suggests that women may be more sensitive to the lipolytic action of the catecholamines. In conclusion, these data support the view that different priorities are placed on lipid and carbohydrate oxidation during exercise in men and women and that these gender-based differences extend to the catecholamine response to exercise.

To investigate the temporal response of the liver to insulin and portal glucose delivery, somatostatin was infused into four groups of 42-h-fasted, conscious dogs ( n ϭ 6/group), basal insulin and glucagon were replaced intraportally, and hyperglycemia was created via a peripheral glucose infusion for 90 min (period 1). This was followed by a 240-min experimental period (period 2) in which hyperglycemia was matched to period 1 and either no changes were made (CON), a fourfold rise in insulin was created (

The underlying causes of nonalcoholic fatty liver disease are unclear, although recent evidence has implicated the endoplasmic reticulum in both the development of steatosis and progression to nonalcoholic steatohepatitis. Disruption of endoplasmic reticulum homeostasis, often termed ER stress, has been observed in liver and adipose tissue of humans with nonalcoholic fatty liver disease and/or obesity. Importantly, the signaling pathway activated by disruption of endoplasmic reticulum homeostasis, the unfolded protein response, has been linked to lipid and membrane biosynthesis, insulin action, inflammation, and apoptosis. Therefore, understanding the mechanisms that disrupt endoplasmic reticulum homeostasis in nonalcoholic fatty liver disease and the role of the unfolded protein response in the broader context of chronic, metabolic diseases have become topics of intense investigation. The present review examines the endoplasmic reticulum and the unfolded protein response in the context of nonalcoholic fatty liver disease.

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In the present study, the time course of change in sucrose-induced insulin resistance, triglyceride (TG) concentration, and liver fatty acid composition was examined. Male rats (n = 8-10/group per time point) was fed a high-starch (ST) diet for 2 wk and were then equicalorically fed ST or a high-sucrose (SU) diet for 1, 2, 5, or 8 wk. Body weight and percent body fat were similar between ST and SU diets at all time points. Glucose infusion rate (GIR) was significantly (P < 0.05) lower in the SU diet (9.2 +/- 0.9, 7.4 +/- 0.5, 6.2 +/- 1.0, and 6.0 +/- 0.9 mg.kg-1.min-1) vs. the ST diet (15.1 +/- 1.7, 15.7 +/- 0.7, 14.7 +/- 1.9, and 14.2 +/- 0.9 mg.kg-1.min-1) at 1, 2, 5, and 8 wk, respectively. Reduced suppression of glucose appearance accounted for 85, 50, 45, and 40% of the reduction in GIR at these same time points. Muscle glycogen synthesis was reduced (P < 0.05 vs. ST diet) in the SU diet at 2, 5, and 8 wk. Fasting plasma TG concentration was inversely related (r = -0.79, P < 0.001) to muscle glycogen synthesis, and liver TG concentration was positively related (r = 0.59, P < 0.01) to glucose appearance. Liver fatty acid composition was similar between diet groups. In summary, the SU diet produced insulin resistance in liver before muscle. TG concentration appears to be related to sucrose-induced insulin resistance in liver and muscle.