Divergent roles of RIPK3 and MLKL in high-fat diet-induced obesity and MAFLD in mice

Tye, H; Conos, SA; Djajawi, TM; Gottschalk, TA; Abdoulkader, N; Kong, IY; Kammoun, HL; Narayana, VK; Kratina, T; Speir, M; Emery, J; Simpson, DS; Hall, C; Vince, AJ; Russo, S; Crawley, R; Rashidi, M; Hildebrand, JM; Murphy, JM; Whitehead, L; De Souza, DP; Masters, SL; Samson, AL; Lalaoui, N; Hawkins, ED; Murphy, AJ; Vince, JE; Lawlor, KE

Author(s): Tye, H; Conos, SA; Djajawi, TM; Gottschalk, TA; Abdoulkader, N; Kong, IY; Kammoun, HL; Narayana, VK; Kratina, T; Speir, M; Emery, J; Simpson, DS; Hall, C; Vince, AJ; Russo, S; Crawley, R; Rashidi, M; Hildebrand, JM; Murphy, JM; Whitehead, L; De Souza, DP; Masters, SL; Samson, AL; Lalaoui, N; Hawkins, ED; Murphy, AJ; Vince, JE; Lawlor, KE;
Details: Publication Year 2025-01,Volume 8,Issue #1,Page e202302446
Journal Title: Life Science Alliance
Publication Type: Research article
Abstract: Cell death frequently occurs in the pathogenesis of obesity and metabolic dysfunction-associated fatty liver disease (MAFLD). However, the exact contribution of core cell death machinery to disease manifestations remains ill-defined. Here, we show via the direct comparison of mice genetically deficient in the essential necroptotic regulators, receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL), as well as mice lacking apoptotic caspase-8 in myeloid cells combined with RIPK3 loss, that RIPK3/caspase-8 signaling regulates macrophage inflammatory responses and drives adipose tissue inflammation and MAFLD upon high-fat diet feeding. In contrast, MLKL, divergent to RIPK3, contributes to both obesity and MAFLD 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.
Keywords: Animals; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics; *Diet, High-Fat/adverse effects; *Obesity/metabolism/etiology/genetics; *Protein Kinases/metabolism/genetics; Mice; Mice, Knockout; Caspase 8/metabolism/genetics; Male; Mice, Inbred C57BL; Signal Transduction; Fatty Liver/metabolism/etiology/genetics; Inflammation/metabolism/genetics; Liver/metabolism/pathology; Macrophages/metabolism; Necroptosis/genetics; Apoptosis/genetics; Adipose Tissue/metabolism; Non-alcoholic Fatty Liver Disease/metabolism/etiology/genetics
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.26508/lsa.202302446
Open Access at Publisher's Site: https://doi.org/10.26508/lsa.202302446
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-12-19 05:48:20

Last Modified: 2024-12-19 05:48:41