Cholesterol overload in macrophages drives metabolic dysfunction-associated steatohepatitis via inhibiting 7-dehydrocholesterol reductase in mice DOI Creative Commons

X. Li,

Kai Wang,

Yunhong Sun

et al.

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Nov. 29, 2024

Dietary cholesterol promotes metabolic dysfunction-associated steatohepatitis (MASH), with hepatic macrophages central to disease pathology. However, the mechanisms by which cholesterol-loaded influence MASH remain unclear. In this study, mice were fed a cholesterol-rich choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Hepatic levels, inflammatory markers, and pro-inflammatory macrophage polarization assessed. vitro studies examined impact of on polarization, identifying 7-dehydrocholesterol reductase (DHCR7) as key cholesterol- inflammation-responsive enzyme. DHCR7 expression in from patients model was evaluated. Functional involving knockdown overexpression experiments, complemented using myeloid-specific knockout mice. RNA sequencing performed liver tissues wild-type identify affected signaling pathways. CDAHFD-fed exhibited local accumulation phenotype liver. Cholesterol overload promoted M1 inflammation, reversible simvastatin. expression, responded state, downregulated M1-polarized suppression phenotype, while its showed anti-inflammatory effects. Myeloid-specific deficiency worsened inflammation infiltration. identified phosphoinositide 3-kinase (PI3K) pathway DHCR7-regulated effects, DHCR7-PI3K axis activation mitigating cholesterol-driven inflammation. These findings unveil novel mechanistic insights into pathogenesis, suggesting targeting macrophage-specific may offer promising therapeutic strategy for MASH.

Language: Английский

Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair DOI Creative Commons
Federico F. De Ponti, Anna Bujko, Zhuangzhuang Liu

et al.

Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Our understanding of the functional heterogeneity resident versus recruited macrophages in diseased liver is limited. A population lipid-associated (LAMs) has been reported to populate alongside Kupffer cells (KCs). However, precise roles these distinct macrophage subsets remain elusive. Here, using proteogenomics, we have identified LAMs multiple models injury. Moreover, found that this phenotype not specific macrophages, as a subset KCs can also adopt LAM-like mouse and human liver. By combining genetic targeting populations, determined both play crucial tissue repair. Specifically, triggering receptor expressed on myeloid 2 (TREM2) expression either or required for efficient clearance dying cells, enhancing repair preventing exacerbated fibrosis.

Language: Английский

Citations

3
TREM2 modulates macrophage pyroptosis and inflammatory responses to ameliorate aortic valve calcification DOI
Jinhui Bian, Chunze Yuan, Jiaxi Gu

et al.

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 149, P. 114161 - 114161

Published: Feb. 6, 2025

Language: Английский

Citations

0
Role of triggering receptor expressed on myeloid cells 2 in the pathogenesis of non-alcoholic fatty liver disease DOI
Lihui Zhang, Sutong Liu, Qing Zhao

et al.

World Journal of Hepatology, Journal Year: 2025, Volume and Issue: 17(2)

Published: Feb. 20, 2025

Non-alcoholic fatty liver disease (NAFLD) is a progressive disease. Without effective interventions, NAFLD can gradually develop to non-alcoholic steatohepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. It still investigate the precise molecular mechanism behind pathophysiology of NAFLD. Triggering receptor expressed on myeloid cells 2 (TREM2) sense tissue injury mediate immune remodeling, thereby inducing phagocytosis, lipid metabolism, metabolic transfer, promoting cell survival combating inflammatory activation. might as result TREM2's regulatory role. We here briefly summarize biological characteristics TREM2 its functions in progression Moreover, we propose broaden therapeutic strategy for by targeting TREM2.

Language: Английский

Citations

0
TREM2 Activation Relieves TMJOA by Stabilizing the Synovial Barrier via Siglec1 DOI
Xinhui Liu, Xinyue Luo, Mang Xiao

et al.

Journal of Dental Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Triggering receptor expressed on myeloid cells 2 (TREM2) is an immune that plays a vital role in innate responses. This study aims to investigate the effect of TREM2 synovial barrier homeostasis and synovitis during temporomandibular joint osteoarthritis (TMJOA). The expression level decreased synovium both patients with TMJOA mouse model TMJOA, accompanied by breakdown. overexpression inhibits macrophage inflammatory response ex vivo relieves inflammation, cartilage degeneration, destruction monosodium iodoacetate–induced mice. RNA-seq analysis reveals Siglec1 serves as downstream signal downregulated after activation. Further vitro experiments demonstrate rhSiglec1 treatment promotes synthesis release cytokines, such interleukin-6 RANTES, macrophages reverses alleviation activation disorders, degradation, bone destruction. Overall, this verifies alleviates pathology maintaining inhibiting inflammation. These findings provide new insight into mechanism pathogenesis TMJOA.

Language: Английский

Citations

0
Myeloid cell path to malignancy: insights into liver cancer DOI Creative Commons
Christel Ramirez, Leila Akkari

Trends in cancer, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
A robust diagnostic model for high-risk MASH: integrating clinical parameters and circulating biomarkers through a multi-omics approach DOI
Jie Zhang, Wei Wang, Xiaoqing Wang

et al.

Hepatology International, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Language: Английский

Citations

0
Special correlation between diet and MASLD: positive or negative? DOI Creative Commons
Jia Liu,

C. S. Li,

Yun Yang

et al.

Cell & Bioscience, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 12, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic and systemic metabolic characterized by the presence of hepatic steatosis at least one cardiometabolic risk factor (CMRF). The pathogenesis MASLD involves multiple mechanisms, including lipid metabolism disorders, insulin resistance, inflammatory responses, hepato-intestinal axis dysfunction. Among these factors, diet serves as both an inducement potential remedy in disease's development. Notably, high-lipid exacerbates fat accumulation, oxidative stress, thereby promoting progression MASLD. Consequently, dietary induction models have become vital tools for studying pathological mechanisms MASLD, providing foundation identifying therapeutic targets. Additionally, we summarize effects optimization on elucidate role specific components regulating axis, metabolism, inhibiting responses. In conclusion, studies utilizing animal offer significant insights into therapy, particularly concerning regulation metabolism-related hepatoenteric axis-related signaling pathways well beneficial mechanism probiotics regulation. By understanding which different patterns affect can assess clinical applicability current strategies provide new directions research treatment aimed modification.

Language: Английский

Citations

0
Linoleic acid inhibits lipopolysaccharide-induced inflammation by promoting TLR4 regulated autophagy in murine RAW264.7 macrophages DOI Creative Commons

Qin Yin,

Kexin Li, Qiuhong Zhang

et al.

Journal of Applied Biomedicine, Journal Year: 2024, Volume and Issue: 22(4), P. 185 - 196

Published: Dec. 18, 2024

Linoleic acid (LA), an essential fatty acid, has emerged as a pivotal regulator in disorders associated with inflammation recent years; however, the underlying mechanisms are still not completely understood. We utilized network pharmacology and experimental methodologies to elucidate anti-inflammatory effects of LA. Our analysis revealed that LA shares common targets sepsis. These enriched various pathways comprising C-type signaling pathway, PI3K-Akt toll-like receptor neutrophil extracellular trap formation, AMPK autophagy-animal. findings suggest may exert regulatory on autophagy during Subsequently, we established vivo ex models sepsis using lipopolysaccharide (LPS) study. Treatment reduced lung damage mice LPS-induced injury, tumor necrosis factor-α (TNF-α) interleukin-6 (IL-6) plasma, bronchoalveolar lavage fluid (BALF), peritoneal (PLF). also decreased production TNF-α IL-6 RAW264.7 macrophages exposed LPS. In macrophages, induced elevation LC3-II while causing reduction p62, which was downregulation 4 (TLR4). 3-methyladenine (3-MA) inhibit autophagic activity, reversed modulatory p62. 3-MA prevented decline TLR4 expression along pro-inflammatory cytokines secretion. activation by lead TLR4, thereby exerting its effects.

Language: Английский

Citations

1
Bioinformatics combined with single-cell analysis reveals the molecular mechanism of pyroptosis in hepatocellular carcinoma DOI Creative Commons

Wei Luo,

Junxia Wang, Hongfei Wang

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 13, 2024

Abstract Purpose Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death, and its molecular mechanisms have not been fully elucidated. The aim this work to discover association between immune microenvironment changes pyroptosis in HCC. Methods Select gene expression profiles from comprehensive database, establish protein-protein interaction networks, perform functional enrichment analysis using databases such as Kyoto Encyclopedia Genes Genomes (KEGG). Single cell identification HCC types malignant cells, trajectory intercellular signal communication further analyze cells liver cells. Bioinformatics combined with single-cell elucidate mechanism underlying development Results key hub genes were validated through immunohistochemistry vitro experiments. Molecular biology has identified six focal death Enrichment shows that intersecting are enriched responses, chemokine mediated signaling pathways, inflammatory responses. cellular clustering single revealed infiltration especially polarization macrophages, which plays an important role. Immunohistochemistry suggests HMGB1, CYCS, GSDMD, IL-1β, NLRP3, IL18 link macrophage during development. Conclusions In summary, main pathogenesis infiltration, particularly promotes secretion factors hepatocyte pyroptosis. Our study may guide future research on pathway

Language: Английский

Citations

0
Cholesterol overload in macrophages drives metabolic dysfunction-associated steatohepatitis via inhibiting 7-dehydrocholesterol reductase in mice DOI Creative Commons

X. Li,

Kai Wang,

Yunhong Sun

et al.

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Nov. 29, 2024

Dietary cholesterol promotes metabolic dysfunction-associated steatohepatitis (MASH), with hepatic macrophages central to disease pathology. However, the mechanisms by which cholesterol-loaded influence MASH remain unclear. In this study, mice were fed a cholesterol-rich choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Hepatic levels, inflammatory markers, and pro-inflammatory macrophage polarization assessed. vitro studies examined impact of on polarization, identifying 7-dehydrocholesterol reductase (DHCR7) as key cholesterol- inflammation-responsive enzyme. DHCR7 expression in from patients model was evaluated. Functional involving knockdown overexpression experiments, complemented using myeloid-specific knockout mice. RNA sequencing performed liver tissues wild-type identify affected signaling pathways. CDAHFD-fed exhibited local accumulation phenotype liver. Cholesterol overload promoted M1 inflammation, reversible simvastatin. expression, responded state, downregulated M1-polarized suppression phenotype, while its showed anti-inflammatory effects. Myeloid-specific deficiency worsened inflammation infiltration. identified phosphoinositide 3-kinase (PI3K) pathway DHCR7-regulated effects, DHCR7-PI3K axis activation mitigating cholesterol-driven inflammation. These findings unveil novel mechanistic insights into pathogenesis, suggesting targeting macrophage-specific may offer promising therapeutic strategy for MASH.

Language: Английский

Citations

0