Lipid accumulation adapts hepatocytes to ER stress Anjana Ramdas Nair Leonore Wünsche Kirsten C Sadler Jeremy Teo 10.6084/m9.figshare.12150639.v1 https://tagc2020.figshare.com/articles/poster/Lipid_accumulation_adapts_hepatocytes_to_ER_stress/12150639 I am Anjana, a Post-Doc in Kirsten Sadlers Lab based in New York University Abu Dhabi. I would like to thank the organizers for giving me the opportunity to present my work as a poster in this very new virtual format. Unfolded protein Respose(UPR) as we all know is activated when there is a lot of unfolded proteins in the ER due to stress in the form of mutations, environmental factors or insults in the form of high fat diet or alcohol. Chronic UPR has been associated with disease such as diabetes and Fatty liver disease. We also know that UPR is a complex mechanism that transitions through different subclasses namely, homeostasis, adaptive and terminal depending on the severity of the stress. However, to this day, it is taken for granted that fat accumulation means UPR has shifted to the dark side. There has never been a clear correlation between UPR Molecular knowledge, to ER morphology and clinical fatty liver. And for this purpose, we use zebrafish liver as a model system. The most exciting aspect for me, is that they are transparent and so I can see development and this makes it a great model for live imaging. More importantly, Zebrafish liver resembles the human liver and over the years, our lab and others have successfully established both pharmacological and genetic interventions to cause fat accumulation in zebrafish liver. Hence combining the powers of live imaging and Gene expression by RNA-seq on livers dependent on their phenotypic outcome, we are trying to tackle the age old question ‘is FAT actually indicative of UPR dysfunction or just a response to UPR activity? ‘. We assessed ER morphology (using transgenic fish expressing a ER localization signal in hepatocyte specifically and lipid accumulation( using Nile Red a live dye) status across 5 different stress agents including ethanol and arsenic. We observe the formation of punctate ER signal in both arsenic and Tm- treatedhepatocytes. However, there was heterogeneity of this phenotype in the population and we wondered if the heterogenous response was indicative of a differential based on the ER phenotype. Similar heterogeneity was observed also in lipid accumulation within the treated population. Segregation of livers based on either ER or lipid accumulation revealed that liver with no lipid accumulation and severe ER malformation associated with higher UPR gene expression indicative of an active UPR response. This was confirmed by qPCR and RNA-seq. Over expression of transcription factor nAtf6 , nuclear form of Atf6 that is one of UPR sensors revealed that it was sufficient to protect against ER deformation. We also found that pre treatment with a stress protected against subsequent lipid accumulation establishing a protective UPR. I am currently working on figuring out the role of lipid and UPR activation. The working model as of now is that lipid accumulation is indicative of a protective UPR. <br> 2020-04-20 21:30:53 Unfolded Protein Response (UPR) Zebrafish Liver Fatty Liver Disease Diseases Gastroenterology and Hepatology Molecular Targets