Curson, J. E. | bioRxiv Science

bioRxiv2026

Defensive lipid droplets are PUFA reservoirs driving bacterial clearance and inflammation

Lipid droplets (LDs) rapidly form in infected cells to participate in the defence against microbes. Here, we investigate the involvement of LD lipids in these immune responses. Comparative shotgun and targeted lipidomics demonstrate that in vivo host LDs accumulate polyunsaturated fatty acids (PUFAs). PUFAs arrive at cells from the bloodstream to be further metabolised into complex PUFAs accrued by LD-triglycerides and -phospholipids. Host lipid metabolism is transcriptionally controlled by rapid, transient, and intricate immune programs initiated by pathogen-associated molecular patterns and relayed by cytokines such as interferons (type I and II), interleukins (IL-1{beta}), and tumour necrosis factor. When this lipid and signalling environment is reproduced in cultured macrophages, newly formed LDs accumulate defensive proteins, coordinate the synthesis of complex PUFAs, and become PUFA reservoirs and suppliers. Among LD-PUFAs, the {omega}-6 arachidonic acid is the most actively metabolised during the initial phases of innate immunity. Released from LDs by adipose triglyceride lipase, arachidonic acid is used by macrophages for prostaglandin synthesis, bacterial phagocytosis, and elimination of microbes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/711356v2_ufig1.gif" ALT="Figure 1"> View larger version (107K): org.highwire.dtl.DTLVardef@14d65eorg.highwire.dtl.DTLVardef@5ecc1org.highwire.dtl.DTLVardef@fa99e5org.highwire.dtl.DTLVardef@8d9632_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet-induced obesity

ObjectivesHistone deacetylase 7 (HDAC7), a classical HDAC family member, promotes LPS-inducible glycolysis and inflammatory mediator production in macrophages, innate immune cells that contribute to pathology in metabolic diseases. Here, we investigated myeloid HDAC7 functions in obesity-driven metabolic disease. MethodsWe used gain- and loss-of-function genetic approaches in mice to investigate myeloid HDAC7 functions in hepatic inflammation and metabolic disease, as well as associations with hepatic gene signatures characteristic of advanced chronic liver disease (CLD). ResultsTransgenic expression of Hdac7 in myeloid cells increased liver inflammation and liver mRNA levels of Ccl2 and Il1b, key inflammatory mediators linked to CLD. Liver glycogen levels were also decreased, another feature of CLD. Transgenic expression of Hdac7 in myeloid cells mimicked the hepatic inflammatory phenotype that was observed in mice fed a high fat, high cholesterol, and high sucrose (HFHCHS) diet, an obesity model that mimics some features of metabolic dysfunction-associated steatotic liver disease. In myeloid Hdac7 transgenic mice fed a HFHCHS diet, relative weight gain was increased, fasted glucose levels were elevated and glucose tolerance was dysregulated by comparison to control mice. Conversely, fasted blood glucose levels were reduced and glucose tolerance was improved in myeloid Hdac7-deleted mice on a HFHCHS diet. HDAC7 mRNA levels were also elevated in the livers of people with advanced CLD and spatial transcriptomics revealed that myeloid HDAC7 directs hepatic gene signatures characteristic of advanced CLD. ConclusionsMyeloid HDAC7 contributes to hepatic inflammation and systemic glucose dysregulation in a mouse model of obesity and liver inflammation.

immunology↗