Transcriptomic analysis of co-culture generated lipid-associated macrophages (LAMs)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE260823 | GEO | 2026/03/18
REPOSITORIES: GEO
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Project description:Transcriptomic analysis of co-culture generated lipid-associated macrophages (LAMs)
| PRJNA1083573 | ENA
Project description:The role of lipid associated macrophages (LAMs) in metabolic homeostasis remains an important yet understudied aspect of adipose tissue. Here, we report a potential new regulatory mechanism by which LAM control adipose tissue homeostasis, involving the endocrine disrupting chemical (EDC) dicyclohexyl phthalate (DCHP) and resulting in altered metabolic regulation. Prepubertal DCHP exposure decreased adipose tissue mass and increased plasma triglycerides in mice. Mechanistically, DCHP facilitated the formation of LAMs. And LAMs communicated with adipocyte precursors, especially adipose progenitor cells, via ApoE-APP interaction, leading to abnormal adipogenesis. Blocking LAMs formation via macrophage-specific PPARγ knockout enabled adaptive adipogenesis, ameliorating DCHP-induced metabolic disorder. Our data highlight the essential role of LAMs in inhibiting adaptive adipogenesis, providing a scientific basis for EDC-induced metabolic dysfunction and phthalates toxicity.
2024-11-01 | GSE246564 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LAL-D). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal-/- mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal-/- mice exhibited CE accumulation and an increased number of macrophages in the liver without significantly affecting liver injury. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. The results suggest that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver, and KC depletion further aggravates hepatic CE levels and dyslipidemia, a finding also supported by our proteomics analysis.
2024-12-01 | PXD056343 | Pride
Project description:Primary human hepatocytes from healthy and Metabolic dysfunction associated steatotic liver disease (MASLD) patients (6 donors each) as 3D spheroids treated with troglitazone (3 concentrations, 0.1xCmax, Cmax and 10xCmax) and vehicle for 7 h. Data for Figure 5 in connected publication.
2026-01-16 | E-MTAB-15610 | biostudies-arrayexpress
Project description:Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a growing global health concern. Increased de novo lipogenesis (DNL), largely mediated by Sterol Regulatory Element-Binding Protein 1 (SREBP1), is a hallmark of MASLD. However, the post-translational mechanisms regulating SREBP1 turnover remain poorly understood. The endoplasmic reticulum-associated degradation (ERAD) pathway ensures protein quality and quantity control, yet its role in hepatic lipid metabolism remains elusive. Here, we investigate the function of the ERAD-specific E3 ubiquitin ligase MARCHF6 in hepatic lipid homeostasis and MASLD pathogenesis.We found hepatic MARCHF6 expression was significantly reduced in both MASLD mouse models and human patients. Liver-specific Marchf6 deletion aggravated hepatic lipid accumulation, fibrosis, and inflammation. Transcriptomic and proteomic analyses revealed upregulation of lipogenic genes in Marchf6Alb livers, with a marked increase in SREBP1 protein levels. Mechanistically, MARCHF6 directly interacted with and ubiquitinated SREBP1, targeting it for proteasomal degradation. Loss of MARCHF6 prolonged SREBP1 half-life, driving excessive DNL.
2026-05-28 | GSE319144 | GEO
Project description:Background & Aims: Spatial location of steatosis is closely related to the progression of metabolic dysfunction-associated steatohepatitis (MASH), and reports suggest lipid-associated macrophages (LAMs) facilitate this progression. However, the underling mechanisms remain elusive. Approach & Results: Spatial transcriptomics (ST) data revealed a significant increase in myeloid cells and MASH-related genes in the hepatic periportal (PP) zone of MASH mice, suggesting a vital role of PP zone in the MASH progression. Thrsp (Spot14), involved in fatty acid synthesis, was markedly elevated in the livers of MASH patients and mice. Notably, CellPhoneDB analysis identified strong interactions between Cd74 and macrophage migration inhibitory factor (MIF) within Thrsp-high zone. Furthermore, Thrsp, Cd74, Mif, Col3a1 and LAMs markers were prominently co-localized in hepatic PP zone of MASH mice, suggesting Thrsp-mediated crosstalk in this region played crucial role in MASH progression. Hepatic Thrsp overexpression/knockout experiments confirmed that Thrsp drove MASH progression by recruiting Cd74+ LAMs mediated by MIF. Mechanistically, Thrsp promoted hepatic palmitic acid (PA) synthesis, mainly by promoting hepatic de novo lipogenesis, and disturbing the binding of FASN-TRIM21, thereby inhibiting FASN’s ubiquitination. Cd74+ LAMs were activated and recruited by chemokine-like MIF secreted from hepatocytes and macrophages stimulated with PA. Additionally, the compound C6 identified as a Thrsp inhibitor, significantly ameliorated MASH in mice. Conclusions: Our study demonstrates that Thrsp drives MASH progression by recruiting Cd74+ LAMs mediated by MIF in hepatic PP zone, providing novel insights into the spatial zonation and crosstalk between lipogenic hepatocytes and LAMs that may result in novel therapies for MASH.
2025-12-05 | GSE293203 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a clinicopathological syndrome characterized by abnormal accumulation of fat within hepatocytes, and there is currently no standardized clinical treatment available. Consequently, there is an urgent need to discover new pharmacological interventions and to investigate novel therapeutic targets for MASLD. Melatonin, known for its multifaceted biological functions, has shown therapeutic potential for the treatment of MASLD. However, the underlying mechanisms remain unclear, particularly since the direct targets of melatonin have not yet been discovered. In our study, we found that melatonin significantly improved various indicators in a mouse MASLD model and protected palmitic acid induced mouse hepatocytes from lipid accumulation. We successfully identified and validated the mitochondrial trifunctional enzyme α-subunit HADHA as a binding target for melatonin using the cellular thermal shift assay (CETSA). This interaction enhances the expression of PGC-1α, which subsequently promotes mitochondrial biogenesis and accelerates lipid metabolism. In addition, melatonin reduces lipid accumulation and ameliorates MASLD through its regulatory effect on key proteins involved in fatty acid metabolism, including Acyl coenzyme A oxidase 1, CD36, and Fatty acid synthase. Importantly, these beneficial effects are diminished when HADHA is knocked down. In conclusion, our study suggests that melatonin ameliorates MASLD through HADHA-mediated regulation of mitochondrial biogenesis and lipid oxidation, highlighting its potential as a promising therapeutic agent for MASLD. These results lay a theoretical foundation and offer novel insights and strategies into the role of melatonin in the treatment of MASLD.
2026-06-08 | PXD071550 | Pride
Project description:Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity and lack of specific markers have made them difficult to target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using in vitro and in vivo models and show that it tracks with MASLD progression/regression across mouse models and large human cohorts. Single-nucleus RNA-sequencing and functional studies reveal that SHGS+ hepatocytes originate from p21+ cells, lose key liver functions and release factors that drive disease progression. One such factor, GDF15, increases in circulation alongside SHGS+ burden and disease progression. Through chemical screening, we identify senolytics that selectively eliminate SHGS+ hepatocytes and improve MASLD in mice. Notably, SHGS enrichment also correlates with dysfunction in other organs. These findings establish SHGS+ hepatocytes as key drivers of MASLD and highlight a potential therapeutic strategy for targeting senescent cells in liver disease and beyond.
2025-02-21 | GSE288534 | GEO
Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 30% of the global population and has emerged as a significant public health concern. It is a multifactorial pathological condition driven by various molecular influencers. Thus, identifying and understanding the molecular drivers of MASLD pathogenesis is essential for developing targeted therapeutic strategies. Here, we elucidate the role of apoptosis antagonizing transcription factor (AATF) as a molecular driver in the pathogenesis of MASLD. Liver-specific silencing of AATF reduced body weight, liver weight, and insulin resistance in WD mice compared to WD controls. Biochemical, histological, and molecular analyses showed reduced liver injury, and steatosis. Transcriptomics analysis showed reduced cellular stress response, inflammation and fibrosis in WDsiAATF. Furthermore, untargeted metabolomics revealed increased biosynthesis of glycerophospholipids and promoted fatty acid oxidation while reducing the triglyceride accumulation. These findings show a molecular link between AATF and hepatic lipid metabolism, implying that AATF could be a promising therapeutic target for MASLD.
2026-02-18 | GSE280320 | GEO
Project description:Analyze human biopsies for the investigation of metabolic dysfunction-associated steatotic liver disease (MASLD). We also analyzed plasma samples for biomarker discovery. And analyzed the role of the impact of the adipose tissue on plasma proteins in relation to MASLD
2025-03-05 | PXD051911 | Pride