| Autor: |
Hazel Tye, Stephanie A. Conos, Tirta M. Djajawi, Nasteho Abdoulkader, Isabella Y. Kong, Helene L. Kammoun, Vinod K. Narayana, Mary Speir, Timothy A. Gottschalk, Jack Emery, Daniel S. Simpson, Cathrine Hall, Angelina J. Vince, Sophia Russo, Rhiannan Crawley, Maryam Rashidi, Joanne M. Hildebrand, James M. Murphy, Lachlan Whitehead, David P. De Souza, Seth L. Masters, Edwin D. Hawkins, Andrew J. Murphy, James E. Vince, Kate E. Lawlor |
| Rok vydání: |
2023 |
| DOI: |
10.1101/2023.03.14.532682 |
| Popis: |
Cell death frequently occurs in the pathogenesis of obesity and non-alcoholic fatty liver disease (NAFLD). However, the exact contribution of core cell death machinery to disease manifestations remains ill-defined. Here, we showviathe direct comparison of mice genetically deficient in apoptotic caspase-8 in myeloid cells, or the essential necroptotic regulators, Receptor-interacting protein kinase-3 (RIPK3) and Mixed lineage kinase domain-like (MLKL), that RIPK3-caspase-8 signaling regulates macrophage inflammatory responses and drives adipose tissue inflammation and NAFLD upon high-fat diet feeding. In contrast, MLKL, divergent to RIPK3, contributes to both obesity and NAFLD in a manner largely independent of inflammation. We also uncover that MLKL regulates the expression of molecules involved in lipid uptake, transport and metabolism and, congruent with this, we discover a shift in the hepatic lipidome upon MLKL deletion. Collectively, these findings highlight MLKL as an attractive therapeutic target to combat the growing obesity pandemic and metabolic disease. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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