title: Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish.
abstract: Fatty liver disease (FLD) is characterized by lipid accumulation in hepatocytes and is accompanied by secretory pathway dysfunction, resulting in induction of the unfolded protein response (UPR). Activating transcription factor 6 (ATF6), one of three main UPR sensors, functions to both promote FLD during acute stress and reduce FLD during chronic stress. There is little mechanistic understanding of how ATF6, or any other UPR factor, regulates hepatic lipid metabolism to cause disease. We addressed this using zebrafish genetics and biochemical analyses and demonstrate that Atf6 is necessary and sufficient for FLD. atf6 transcription is significantly upregulated in the liver of zebrafish with alcoholic FLD and morpholino-mediated atf6 depletion significantly reduced steatosis incidence caused by alcohol. Moreover, overexpression of active, nuclear Atf6 (nAtf6) in hepatocytes caused FLD in the absence of stress. mRNA-Seq and qPCR analyses of livers from five day old nAtf6 transgenic larvae revealed upregulation of genes promoting glyceroneogenesis and fatty acid elongation, including fatty acid synthase (fasn), and nAtf6 overexpression in both zebrafish larvae and human hepatoma cells increased the incorporation of 14C-acetate into lipids. Srebp transcription factors are key regulators of lipogenic enzymes, but reducing Srebp activation by scap morpholino injection neither prevented FLD in nAtf6 transgenics nor synergized with atf6 knockdown to reduce alcohol-induced FLD. In contrast, fasn morpholino injection reduced FLD in nAtf6 transgenic larvae and synergistically interacted with atf6 to reduce alcoholic FLD. Thus, our data demonstrate that Atf6 is required for alcoholic FLD and epistatically interacts with fasn to cause this disease, suggesting triglyceride biogenesis as the mechanism of UPR induced FLD.
authors.affiliation: Department of Medicine - Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Howarth
authors.affiliation: Department of Medicine - Division of Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Diabetes and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lindtner
authors.affiliation: Department of Medicine - Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Vacaru
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Sachidanandam
authors.affiliation: Department of Medicine - Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Orkhontuya
authors.initials: O
authors.lastname: Tsedensodnom
authors.affiliation: Department of Medicine - Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Taisa
authors.initials: T
authors.lastname: Vasilkova
authors.affiliation: Department of Medicine - Division of Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Diabetes and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
authors.affiliation: Department of Medicine - Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Kirsten C
authors.initials: KC
authors.lastname: Sadler
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D015533:Transcriptional Activation / Q000235:genetics*; D015027:Zebrafish
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000431:Ethanol