Fatty acid-mediated endoplasmic reticulum stress in vivo: differential response to the infusion of Soybean and Lard Oil in rats.

BACKGROUND: In cell systems, saturated fatty acids, compared to unsaturated fatty acids, induce a greater degree of ER stress and inflammatory signaling in a number of cell types, including hepatocytes and adipocytes. The aim of the present study was to determine the effects of infusions of lard oil (enriched in saturated fatty acids) and soybean oil (enriched in unsaturated fatty acids) on liver and adipose tissue ER stress and inflammatory signaling in vivo. METHODS: Lipid emulsions containing glycerol, phosphatidylcholine, antibiotics (Control, n=7) and either soybean oil (Soybean, n=7) or lard oil (Lard, n=7) were infused intravenously into rats over a 4 h period. RESULTS: Plasma free fatty acid levels were 0.5±0.1 mmol/L (mean±SD) in Control and were increased to 1.0±0.3 mmol/L and 1.1±0.3 mmol/L in Soybean and Lard, respectively. Glucose and insulin levels were not different among groups. Markers of endoplasmic reticulum (ER) stress and activation of inflammatory pathway signaling were increased in liver and adipose tissue from Soybean and Lard compared to Control, but were increased to a greater extent in Lard compared to Soybean. CONCLUSIONS: These data suggest that elevated plasma free fatty acids can induce hepatic and adipose tissue ER stress and inflammation in vivo. In addition, saturated fatty acids appear to be more cytotoxic than unsaturated fatty acids in vivo.

Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease.

The incidence of obesity is now at epidemic proportions and has resulted in the emergence of nonalcoholic fatty liver disease (NAFLD) as a common metabolic disorder that can lead to liver injury and cirrhosis. Excess sucrose and long-chain saturated fatty acids in the diet may play a role in the development and progression of NAFLD. One factor linking sucrose and saturated fatty acids to liver damage is dysfunction of the endoplasmic reticulum (ER). Although there is currently no proven, effective therapy for NAFLD, the amino sulfonic acid taurine is protective against various metabolic disturbances, including alcohol-induced liver damage. The present study was undertaken to evaluate the therapeutic potential of taurine to serve as a preventative treatment for diet-induced NAFLD. We report that taurine significantly mitigated palmitate-mediated caspase-3 activity, cell death, ER stress, and oxidative stress in H4IIE liver cells and primary hepatocytes. In rats fed a high-sucrose diet, dietary taurine supplementation significantly reduced hepatic lipid accumulation, liver injury, inflammation, plasma triglycerides, and insulin levels. The high-sucrose diet resulted in an induction of multiple components of the unfolded protein response in the liver consistent with ER stress, which was ameliorated by taurine supplementation. Treatment of mice with the ER stress-inducing agent tunicamycin resulted in liver injury, unfolded protein response induction, and hepatic lipid accumulation that was significantly ameliorated by dietary supplementation with taurine. Our results indicate that dietary supplementation with taurine offers significant potential as a preventative treatment for NAFLD.

Rapamycin inhibits postprandial-mediated X-box-binding protein-1 splicing in rat liver.

Recent studies have linked the unfolded protein response (UPR), in particular the inositol-requiring, endoplasmic reticulum-to-nucleus signaling protein 1alpha (IRE1alpha)-X-box-binding protein-1 (XBP1) branch of the UPR, to the regulation of lipogenesis and hepatic steatosis. In this study, we examined the hypothesis that the postprandial environment can activate the IRE1alpha-XBP1 branch of the UPR in the liver via a mammalian target of rapamycin complex 1 (mTORC1)-dependent mechanism. Toward this end, rats were fed a high-carbohydrate diet (68% of energy from corn starch) for 3 h in the absence or presence of rapamycin (intraperitoneal injection of 1 mg/kg) and liver tissue was taken 1 or 7 h following the feeding period. Feeding activated the mTORC1 pathway and IRE1alpha, induced XBP1 splicing, and increased the expression of XBP1 target genes and lipogenic genes in the liver. The presence of rapamycin prevented the activation of mTORC1 and IRE1alpha, XBP1 splicing, and the increased expression of XBP1 target genes and lipogenic genes. Rapamycin also prevented the feeding-induced increase in nuclear sterol regulatory element binding protein 1c. These data suggest that the postprandial environment promotes activation of the IRE1-XBP1 branch of the UPR in the liver. This activation appears to be mediated in part by mTORC1.

Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death.

Prolonged endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) have been linked to apoptosis via several mechanisms, including increased expression of C/EBP homologous protein (Chop). Increased long-chain fatty acids, in particular saturated fatty acids, induce ER stress, Chop expression, and apoptosis in liver cells. The first aim of the present study was to determine the role of Chop in lipid-induced hepatocyte cell death and liver injury induced by a methionine-choline-deficient diet. Albumin-bound palmitate increased Chop gene and protein expression in a dose-dependent fashion in H4IIE liver cells. siRNA-mediated silencing of Chop in H4IIE liver cells reduced thapsigargin-mediated cell death by approximately 40% and delayed palmitate-mediated cell death, but only at high concentrations of palmitate (400-500 microM). Similar results were observed in primary hepatocytes isolated from Chop-knockout mice. Indices of liver injury were also not reduced in Chop-knockout mice provided a methionine-choline-deficient diet. To ascertain whether ER stress was linked to palmitate-induced cell death, primary hepatocytes were incubated in the absence or presence of the chemical chaperones taurine-conjugated ursodeoxycholic acid or 4-phenylbutyric acid. The presence of either of these chemical chaperones protected liver cells from palmitate-mediated ER stress and cell death, in part, via inhibition of JNK activation. These data suggest that ER stress is linked to palmitate-mediated cell death via mechanisms that include JNK activation.