All transcripts were created with artificial intelligence software and modified with manual review by a third party. Although we make every effort to ensure accuracy with the manual review, some may contain computer-generated mistranslations resulting in inaccurate or nonsensical word combinations, or unintentional language. FASEB and the presenting speakers did not review the transcripts and are not responsible and will not be held liable for damages, financial or otherwise, that occur as a result of transcript inaccuracies.
The ER Stress Transducer ATF6 Promotes Fatty Liver Disease-Driven Cancer
Cynthia Lebeaupin1, Xin Li2, Clementine Druelle-Cedano1, Aikaterini Kadianaki2, Li Gu3, Laura Kim4, Sue Murray5, Celeste Simon4, Michael Karin3, Dirk Haller6, Mathias Heikenwalder2,7*, Randal J. Kaufman1*
1Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA;2Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;3Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA;4Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, 456 BRBII/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA;5Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA;6Chair of Nutrition and Immunology, Technical University of Munich, 85354 Freising, Germany;7The M3 Research Institute, Ottfreid-Mueller Strasse 37, Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany. *Co-corresponding authors
Background: Endoplasmic reticulum (ER) stress plays a crucial role in chronic liver disease and cancer. Overnutrition leading to hepatocyte metabolic overload activates the unfolded protein response (UPR) to process activating transcription factor 6 (ATF6), generating a transcriptionally active nuclear-localized ATF6p50 fragment to enforce adaptive programs.
Aims: While we previously demonstrated ATF6 is required to survive short-term acute ER stress and resolve lipid accumulation (steatosis) in the liver (1,2), the long-term role of ATF6 under chronic ER stress with fatty liver disease progression has not been examined. We hypothesize that activated ATF6 (ATF6p50) promotes protein misfolding and metabolic dysregulation in hepatocytes.
Methods: Mice with hepatocyte-specific and constitutively active ATF6p50 expression (3) or Atf6 deletion were used to explore the role of ATF6 in fatty liver disease progression to hepatocellular carcinoma (HCC). These mice were further crossed with transgenic MUP-uPA mice, an ER stress-driven model of steatosis, inflammation, fibrosis, and HCC upon high-fat diet feeding (4). Human datasets were explored and patient HCC tissue microarrays processed by digital spatial profiling and transcriptomics.
Results: Our recent findings show that chronic ATF6 activation in hepatocytes causes glycogen depletion, lipid accumulation and protein misfolding. Interestingly, restoring gluconeogenesis by adeno-associated viral fructose-1,6-bisphosphatase (5,6) reintroduction to hepatocytes rescued the metabolic phenotype and mitigated ER stress-related induction of ATF6-dependent transcripts and proteins. Furthermore, Atf6-deleted mice fed a high-fat diet were protected against ER stress-driven liver injury, lipid, and collagen accumulation. Livers of MUP-uPA mice treated with ATF6-suppressing compounds were protected against ER stress and tumor burden. Finally, ATF6 activation is present in human HCC and associated with poor prognosis, and distinct RNA signatures characterize ATF6-positive versus ATF6-negative regions of human HCC tissue.
Conclusions: Hence, chronic ATF6 activation promotes fatty liver disease progression to cancer, which is counter-intuitive from its adaptive role in acute ER stress in hepatocytes, thus opening entirely novel objectives for investigation and therapeutic strategies for intervention.
Funding: R01CA198103, Fishman Fund Fellowship
References:
1. Rutkowski et al., UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell (2008).
2. Wu et al., ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell (2007).
3. Coleman et al., Activated ATF6 Induces Intestinal Dysbiosis and Innate Immune Response to Promote Colorectal Tumorigenesis. Gastroenterology (2018).
4. Nakagawa et al., ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development. Cancer Cell (2014).
5. Li et al., Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature (2014).
6. Li et al., FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat Cell Biol (2020).