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Resolvin D1–mediated cellular crosstalk protects against MASH [Bulk RNA-seq]

ABSTRACT: Recent studies have highlighted the beneficial effect of resolvin D1 (RvD1), a DHA-derived specialized pro-resolving mediator, on metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanisms are not well understood. Our study aims to determine the mechanism by which RvD1 protects against MASH progression. RvD1 was administrated to MASH mice, followed by bulk and single-cell RNA sequencing analysis. Primary cells including bone marrow-derived macrophages (BMDMs), Kupffer cells, T cells, and primary hepatocytes were isolated to study the effect of RvD1 on inflammation, cell death, and fibrosis regression genes. RvD1 administration improved MASH features including reducing inflammation, cell death, and liver fibrosis. Mechanistically, RvD1 reduced inflammation by suppressing the stat1-cxcl10 signaling pathway in macrophages and prevented cell death by alleviating ER stress-mediated apoptosis in hepatocytes. Moreover, RvD1 induced Mmp2 and decreased Acta2 expression in hepatic stellate cells (HSCs), and promoted Mmp9 and Mmp12 expression in macrophages, leading to fibrosis regression in MASH. RvD1 reduced stat1-mediated pro-inflammatory response, mitigated ER stress-induced apoptosis, and promotes MMP-mediated fibrosis regression in MASH. Thus, our study highlights the therapeutic potential of RvD1 for MASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE263768 | GEO | 2025/04/25

REPOSITORIES: GEO

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Resolvin D1–mediated cellular crosstalk protects against MASH [scRNA-seq]

Project description:Recent studies have highlighted the beneficial effect of resolvin D1 (RvD1), a DHA-derived specialized pro-resolving mediator, on metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanisms are not well understood. Our study aims to determine the mechanism by which RvD1 protects against MASH progression. RvD1 was administrated to MASH mice, followed by bulk and single-cell RNA sequencing analysis. Primary cells including bone marrow-derived macrophages (BMDMs), Kupffer cells, T cells, and primary hepatocytes were isolated to study the effect of RvD1 on inflammation, cell death, and fibrosis regression genes. RvD1 administration improved MASH features including reducing inflammation, cell death, and liver fibrosis. Mechanistically, RvD1 reduced inflammation by suppressing the stat1-cxcl10 signaling pathway in macrophages and prevented cell death by alleviating ER stress-mediated apoptosis in hepatocytes. Moreover, RvD1 induced Mmp2 and decreased Acta2 expression in hepatic stellate cells (HSCs), and promoted Mmp9 and Mmp12 expression in macrophages, leading to fibrosis regression in MASH. RvD1 reduced stat1-mediated pro-inflammatory response, mitigated ER stress-induced apoptosis, and promotes MMP-mediated fibrosis regression in MASH. Thus, our study highlights the therapeutic potential of RvD1 for MASH.

2025-04-25 | GSE263770 | GEO

Lipid Associated Macrophages' Promotion of Fibrosis Resolution during MASH regression requires TREM2

Project description:While macrophage heterogeneity during Metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage sub- populations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression associated macrophages (RAM) and establish the importance of TREM2+ macrophages during MASH regression. Liver resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte derived macrophage sub-populations. Trem2 is expressed in two macrophage sub- populations: (i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and (ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct MF sub-population emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage sub-population during MASH, they decreased during regression. LAM was the dominant macrophage sub-type during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown like structures (hCLS). TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression, but also for effective regression of inflammation and fibrosis. TREM2+ MF are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic co-ordination with other cell- types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid-handling and collagen degradation.

2024-08-05 | GSE261829 | GEO

Resolvin D1 attenuated liver injury caused by chronic ethanol and acute LPS challenge in mice

Project description:Alcohol-associated liver disease (ALD) is a major health problem with limited effective treatment options. Alcohol-associated hepatitis (AH) is a subset of severe ALD with a high rate of mortality due to infection, severe inflammation, and ultimately multi-organ failure. There is an urgent need for novel therapeutic approaches to alleviate the human suffering associated with this condition. Resolvin D1 (RvD1) promotes the resolution of inflammation and regulates immune responses. The current study aimed to test the therapeutic efficacy and mechanisms of RvD1-mediated effects on liver injury and inflammation in an experimental animal model that mimics severe AH in humans. Our data demonstrated that mice treated with RvD1 had attenuated liver injury and inflammation caused by EtOH and LPS exposure by limiting hepatic neutrophil accumulation and decreasing hepatic levels of pro-inflammatory cytokines. In addition, RvD1 treatment attenuated hepatic pyroptosis, an inflammatory form of cell death, via downregulation of pyroptosis-related genes such as GTPase family member b10 and guanylate binding protein 2, and reducing cleavage of caspase 11 and gasdermin-D. In vitro experiments with primary mouse hepatocytes and bone marrow-derived macrophages confirmed the effectiveness of RvD1 in the attenuation of pyroptosis. In summary, our data demonstrated that RvD1 treatment provided beneficial effects against liver injury and inflammation in an experimental animal model recapitulating features of severe AH in humans. Our results suggest that RvD1 may be a novel adjunct strategy to traditional therapeutic options for AH patients.

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Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism.

Project description:Metabolic dysfunction-associated steatohepatitis (MASH) remains a significant health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption and pharmacological inhibition of SMPD3 alleviate MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. While healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses SIRT1, triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes MASH progression by enhancing caveolae-dependent lipid uptake in hepatocytes and extracellular vesicle secretion from steatotic hepatocytes to worsen inflammation and fibrosis. Thus, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid balance and holds great promise for developing novel MASH therapies.

2025-02-26 | GSE286433 | GEO

Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism

2025-02-26 | GSE271336 | GEO

Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism

2025-02-26 | GSE271335 | GEO

Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism

2025-02-26 | GSE271333 | GEO

Mannose reduces fructose metabolism and reverses MASH in human liver slices and murine models in vivo

Project description:Background & Aims: Fibrosis drives liver-related mortality in metabolic dysfunction-associated steatohepatitis (MASH), yet we have limited medical therapies to target MASH-fibrosis progression. Here we report that mannose, a simple sugar, attenuates MASH steatosis and fibrosis in two robust murine models and human liver slices. Methods: The well-validated FAT-MASH murine model for liver steatosis and fibrosis was employed. Mannose was supplied in the drinking water at the start (“Prevention” group) or at week 6 of the 12-week MASH regimen (“Therapy” group). The in vivo anti-fibrotic effects of mannose supplementation were tested in a second model of carbon tetrachloride (CCl4)-induced liver fibrosis. A quantitative and automated digital pathology approach was used to comprehensively assess steatosis and fibrosis phenotypes. Mannose was also tested in vitro in human and primary mouse hepatocytes conditioned with free fatty acids alone or with fructose, and Human Precision Cut Liver Slices (hPCLS) from patients with end-stage MASH cirrhosis. Results: Oral mannose supplementation improved liver fibrosis in vivo in both FAT-MASH and CCl4 mouse models, as well as in hPCLS MASH samples. Mannose also reduced liver steatosis in FAT-MASH mice, and in human and mouse hepatocytes in vitro. Ketohexokinase (KHK), the main enzyme in fructolysis, was decreased with mannose in whole mouse liver, cultured hepatocytes, and hPCLS. Removal of fructose or overexpression of KHK each abrogated the anti-steatotic effects of mannose. Conclusions: This study identifies mannose as a novel therapeutic candidate for MASH that mitigates steatosis by dampening hepatocyte KHK expression and exerts independent anti-fibrotic effects in two mouse models and human liver tissue slices.

2025-01-31 | GSE287943 | GEO

Lipid Associated Macrophages' Promotion of Fibrosis Resolution during MASH regression requires TREM2

Project description:Lipid Associated Macrophages' Promotion of Fibrosis Resolution during MASH regression requires TREM2

| PRJNA1089178 | ENA

CDA HFD mice analysed for hepatic gene expression after treatment with semaglutide

Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. We show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation, and reduced hepatic expression of fibrosis- and inflammation-related gene pathways.

2025-04-25 | GSE294630 | GEO

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