The acute and chronic exposure protocols had equivalent effects with respect to the induction of UPR target gene expression (Fig. 8B). Steatosis occurred in 81% of the fish treated with the chronic protocol, but it did not occur after a short exposure (protocols B and Selleck BEZ235 C). However, when the TN was washed out (protocol D), 35% of the fish developed steatosis (Fig. 8C). We then tested whether depleting Atf6 affected steatosis caused by acute

TN treatment (protocol D). The percentage of fish with steatosis was significantly reduced among mbtps11487 mutants (45%) versus WT larvae (65%) chronically challenged with TN, but the percentage increased in response to acute TN treatment (85%) in comparison with their WT siblings (42%; Fig. 8D). Similar results were obtained for atf6 morphants: 76% developed steatosis after acute TN treatment, whereas 46% and 52% of the uninjected and control-injected larvae did (Fig. 8D). Thus, Atf6 depletion potentiates steatosis

selleck chemical caused by acute ER stress in both zebrafish and mice.12, 13 We have used zebrafish as a novel tool for understanding the complex relationship between UPR activation and steatosis. Our data demonstrate that both acute and chronic ER stress can lead to steatosis, and they illustrate the opposing roles that Atf6 plays in these different scenarios. We found that Atf6 depletion protects fish from steatosis due to chronic ER stress induced by either foigr mutation or prolonged exposure MCE to TN, but it can accentuate steatosis caused by acute TN treatment. This is an important distinction because most FLD etiologies are likely associated with chronic UPR activation if not frank ER stress. In these cases, attempts to improve

protein folding and reduce UPR signaling are predicted to be therapeutic. Exciting data from mouse models suggest the efficacy of this approach.10, 11, 14, 18 How does chronic UPR activation affect lipid metabolism in the liver? One possibility is that components of the UPR may directly modulate lipid metabolism. Although some studies have implicated lipid synthesis directed by Xbp135 or Srebps17, 18, 36, 37 as a factor in steatosis associated with ER stress, we do not believe that lipid synthesis is a major contributing factor to steatosis in our models. We hypothesize that the foigr mutation and TN treatment induce Atf6, and this in turn may suppress Srebp2 activity; this is consistent with data from mammalian cells.20 Although Atf6 depletion caused a slight up-regulation of Srebp2 target genes, this was insufficient to cause steatosis (see Figs. 7A and 8A,C,D). On the contrary, atf6 morphants were protected from steatosis induced by the foigr mutation. Together, our data suggest that triglyceride and cholesterol synthesis is unlikely to significantly contribute to steatosis caused by chronic ER stress. It is likely that disruption of the secretory pathway prevents lipoprotein secretion.