The Multifaceted Roles of Macrophages in NAFLD Pathogenesis

Vonderlin, Joscha; Chavakis, Triantafyllos; Sieweke, Michael H.; Tacke, Frank

doi:10.1016/j.jcmgh.2023.03.002

Cited by 34 publications

(25 citation statements)

References 151 publications

(211 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Noteworthy, immunometabolism enhancement, especially on myeloid cell populations, was revealed in post-SG steatotic livers. Myeloid cells, especially macrophages, play a pivotal role in pathological and therapeutic mechanisms of metabolic liver diseases (26,31,32). The involvement of liver macrophages can mediate hepatic lipid metabolism during steatotic stress (33,34), while lipid metabolism is closely associated with phenotypic alterations in macrophages (35,36).…”

Section: Discussionmentioning

confidence: 99%

Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy

Chen,

Zeng,

Cai

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive liver disease that encompasses a spectrum of steatosis, steatohepatitis (or MASH), and fibrosis. Evidence suggests that dietary restriction (DR) and sleeve gastrectomy (SG) can lead to remission of hepatic steatosis and inflammation through weight loss, but it is unclear whether these procedures induce distinct metabolic or immunological changes in MASLD livers. This study aims to elucidate the intricate hepatic changes following DR, SG or sham surgery in rats fed a high-fat diet as a model of obesity-related MASLD, in comparison to a clinical cohort of patients undergoing SG. Single-cell and single-nuclei transcriptome analysis, spatial metabolomics, and immunohistochemistry revealed the liver landscape, while circulating biomarkers were measured in serum samples. Artificial intelligence-assisted image analysis characterized the spatial distribution of hepatocytes, myeloid cells and lymphocytes. In patients and experimental MASLD rats, SG improved BMI, circulating liver injury biomarkers and triglyceride levels. Both DR and SG attenuated liver steatosis and fibrosis in rats. Metabolism-related genes (Ppara, Cyp2e1 and Cyp7a1) were upregulated in hepatocytes upon DR and SG, while SG broadly upregulated lipid metabolism on cholangiocytes, monocytes, macrophages, and neutrophils. Furthermore, SG promoted myeloid cell accumulation in the liver not only ameliorating inflammation but activating liver repair processes. Regions with potent myeloid infiltration were marked with enhanced metabolic capacities upon SG. Additionally, a disruption of periportal hepatocyte functions was observed upon DR. In conclusion, this study indicates a dynamic cellular crosstalk in steatotic livers undergoing SG. Notably, PPARalpha- and gut-liver axis-related processes, and metabolically-active myeloid cell infiltration indicate intervention-related mechanisms supporting SG for the treatment of MASLD.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy

Chen,

Zeng,

Cai

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In HCC, pro-inflammatory macrophages foster tumor growth and progression by stimulating angiogenesis and supporting tumor vascularization and growth. Moreover, they prevent antitumor immune responses, establishing a microenvironment favorable for tumor progression ( 49 – 51 ). In our hands, the lack of HRG causes a marked lowering of macrophage infiltration in MASH-related HCCs along with a reduction in the expression of pro-inflammatory cytokines (IL-1β, IL-6, and IL-12) as well as of IL-10 and TREM2, a marker of HCC-associated macrophages ( 45 , 46 ).…”

Section: Discussionmentioning

confidence: 99%

Histidine-rich glycoprotein in metabolic dysfunction-associated steatohepatitis-related disease progression and liver carcinogenesis

Foglia,

Sutti,

Cannito

et al. 2024

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD), previously non-alcoholic fatty liver disease (NAFLD), is a leading cause of chronic liver disease worldwide. In 20%–30% of MASLD patients, the disease progresses to metabolic dysfunction-associated steatohepatitis (MASH, previously NASH) which can lead to fibrosis/cirrhosis, liver failure as well as hepatocellular carcinoma (HCC). Here we investigated the role of histidine-rich glycoprotein (HRG), a plasma protein produced by hepatocytes, in MASLD/MASH progression and HCC development.MethodsThe role of HRG was investigated by morphological, cellular, and molecular biology approaches in (a) HRG knock-out mice (HRG−/− mice) fed on a CDAA dietary protocol or a MASH related diethyl-nitrosamine/CDAA protocol of hepatocarcinogenesis, (b) THP1 monocytic cells treated with purified HRG, and (c) well-characterized cohorts of MASLD patients with or without HCC.ResultsIn non-neoplastic settings, murine and clinical data indicate that HRG increases significantly in parallel with disease progression. In particular, in MASLD/MASH patients, higher levels of HRG plasma levels were detected in subjects with extensive fibrosis/cirrhosis. When submitted to the pro-carcinogenic protocol, HRG−/− mice showed a significant decrease in the volume and number of HCC nodules in relation to decreased infiltration of macrophages producing pro-inflammatory mediators, including IL-1β, IL-6, IL-12, IL-10, and VEGF as well as impaired angiogenesis. The histopathological analysis (H-score) of MASH-related HCC indicate that the higher HRG positivity in peritumoral tissue significantly correlates with a lower overall patient survival and an increased recurrence. Moreover, a significant increase in HRG plasma levels was detected in cirrhotic (F4) patients and in patients carrying HCC vs. F0/F1 patients.ConclusionMurine and clinical data indicate that HRG plays a significant role in MASLD/MASH progression to HCC by supporting a specific population of tumor-associated macrophages with pro-inflammatory response and pro-angiogenetic capabilities which critically support cancer cell survival. Furthermore, our data suggest HRG as a possible prognostic predictor in HCC patients with MASLD/MASH-related HCCs.

show abstract

“…An adverse metabolic milieu affects the immune response, which plays a crucial role in the pathogenesis of NASH. For example, the functional status (“polarization”) of macrophages is influenced by fatty acids, which, in turn, promote the progression of metabolic dysfunction across various phases of disease and in different body tissues [ 110 , 111 , 112 ]. Macrophages play a crucial role in liver fibrosis progression and reversal via IL-4Rα signaling [ 113 ].…”

Section: Nash As a Metabolic Disorder: Epidemiology And Mechanismsmentioning

confidence: 99%

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

Lonardo,

Ballestri,

Mantovani

et al. 2024

Metabolites

View full text Add to dashboard Cite

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular–kidney–metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.

show abstract

The Multifaceted Roles of Macrophages in NAFLD Pathogenesis

Cited by 34 publications

References 151 publications

Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy

Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy

Histidine-rich glycoprotein in metabolic dysfunction-associated steatohepatitis-related disease progression and liver carcinogenesis

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

Contact Info

Product

Resources

About