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Transcriptomic analysis of co-culture generated lipid-associated macrophages (LAMs)

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by profound remodeling of hepatic macrophages, including the emergence of lipid-associated macrophages (LAMs). However, the mechanisms through which LAMs promote fibrosis and their key molecular drivers remain elusive.

ORGANISM(S): Homo sapiens

PROVIDER: GSE260823 | GEO | 2026/03/18

REPOSITORIES: GEO

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Transcriptomic analysis of co-culture generated lipid-associated macrophages (LAMs)

Project description:Transcriptomic analysis of co-culture generated lipid-associated macrophages (LAMs)

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2024-11-01 | GSE246564 | GEO

From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism

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

MIF-mediated crosstalk between Thrsp+ hepatocytes and Cd74+ lipid-associated macrophages in hepatic periportal zone drives MASH

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.

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The Impact of Silencing Hepatic AATF on Transcriptomic and Metabolomic Signatures in Experimental MASH

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2025-04-14 | GSE277560 | GEO

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