Role of immune responses in the development of NAFLD-associated liver cancer and prospects for therapeutic modulation

Yahoo, Neda; Dudek, Michael; Knolle, Percy A.; Heikenwälder, Mathias

doi:10.1016/j.jhep.2023.02.033

Cited by 30 publications

(9 citation statements)

References 193 publications

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“…Immune dysfunction plays a crucial role in the progression of NAFLD and other metabolic disorders, implicating both the innate and adaptive immune systems. [72] We utilized the CIBERSORT algorithm to assess the relationship between key genes and immune cell infiltration in patients with NAFLD, aiming to discern whether modulation of immune regulatory mechanisms could attenuate intrahepatic inflammation, hepatocellular injury, fibrosis, and potentially hepatocarcinogenesis. In patients with NAFLD, we found significant correlations between 2 biomarkers (CD37 and CXCL9) and T cells follicular helper, T cells CD4 memory resting, NK cells activated, Monocytes, Macrophage M1, and activated Dendritic cells.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic value of sphingolipid metabolism-related genes CD37 and CXCL9 in nonalcoholic fatty liver disease

Zhang,

Wang,

Jiang

2024

Medicine

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The development of nonalcoholic fatty liver disease (NAFLD) has been reported to be caused by sphingolipid family inducing insulin resistance, mitochondrial dysfunction, and inflammation, which can be regulated by multiple sphingolipid metabolic pathways. This study aimed to explore the molecular mechanism of crucial sphingolipid metabolism related genes (SMRGs) in NAFLD. Firstly, the datasets (GSE48452, GSE126848, and GSE63067) from the Gene Expression Omnibus database and sphingolipid metabolism genes (SMGs) from previous research were collected for this study. The differentially expressed genes (DEGs) between different NAFLD and controls were acquired through “limma,” and the SMRGs were authenticated via weighted gene co-expression network analysis (WGCNA). After overlapping the DEGs and SMRGs, the causality between the intersection genes (DE-SMRGs) and NAFLD was explored to sort out the candidate biomarkers by Mendelian randomization (MR) study. The receiver operating characteristic (ROC) curves of candidate biomarkers in GSE48452 and GSE126848 were yielded to determine the biomarkers, followed by the nomogram construction and enrichment analysis. Finally, the immune infiltration analysis, the prediction of transcription factors (TFs) and drugs targeting biomarkers were put into effect. A total of 23 DE-SMRGs were acquired based on the differential analysis and weighted gene co-expression network analysis (WGCNA), of which 3 DE-SMRGs (CD37, CXCL9 and IL7R) were picked out for follow-up analysis through univariate and multivariate MR analysis. The values of area under ROC curve of CD37 and CXCL9 were >0.7 in GSE48452 and GSE126848, thereby being regarded as biomarkers, which were mainly enriched in amino acid metabolism. With respect to the Spearman analysis between immune cells and biomarkers, CD37 and CXCL9 were significantly positively associated with M1 macrophages (P < .001), whose proportion was observably higher in NAFLD patients compared with controls. At last, TFs (ZNF460 and ZNF384) of CD37 and CXCL9 and a total of 79 chemical drugs targeting CD37 and CXCL9 were predicted. This study mined the pivotal SMRGs, CD37 and CXCL9, and systematically explored the mechanism of action of both biomarkers based on the public databases, which could tender a fresh reference for the clinical diagnosis and therapy of NAFLD.

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Section: Discussionmentioning

confidence: 99%

Diagnostic value of sphingolipid metabolism-related genes CD37 and CXCL9 in nonalcoholic fatty liver disease

Zhang,

Wang,

Jiang

2024

Medicine

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“…As liver function was associated with PFS, the same types of analysis were performed restricted to Child-Pugh A patients with cirrhosis. 16 [10][11][12][13][14][15][16][17][18][19][20][21][22][23] 15 [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] 15 [11][12][13][14][15][16][17][18][19][20][21][22][23] 12 [8][9][10][11][12][13][14][15][16] 15…”

Section: The Presence Of Masld Was Not Associated With Pfsmentioning

confidence: 99%

“…Furthermore, these cells might contribute to the reduced efficacy of ICIs. 5,8 The potential influence of aetiology on the response to ICI-based therapy was also underscored in the subgroup analysis of the IMbrave 150 trial. 1,14 The study successfully met its endpoint, demonstrating a superior OS differences in PFS and OS according to the aetiology.…”

Section: No Impact Of Mrf or Masld On The Occurrence Of Immune-relate...mentioning

confidence: 99%

No correlation between MASLD and poor outcome of Atezolizumab‐Bevacizumab therapy in patients with advanced HCC

Copil,

Campani,

Lequoy

et al. 2024

Liver International

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IntroductionIt has been suggested that in patients with hepatocellular carcinoma (HCC) of metabolic aetiology, the efficacy of immunotherapy may be reduced. The aim was to investigate the impact of metabolic‐associated steatotic liver disease (MASLD) and metabolic risk factors (MRF) on the outcomes of Atezolizumab‐Bevacizumab (AtezoBev).MethodsWe collected data from 295 AtezoBev‐treated patients, starting in 2020. MASLD was defined by the current/past presence of MRF, namely BMI ≥ 30 kg/m2, type 2 diabetes, arterial hypertension or dyslipidaemia and no other cause of liver disease (daily alcohol ≤30 g in males and ≤20 g in females). The influence of baseline characteristics on progression (PFS) and overall survival (OS) was assessed by uni/multivariate analysis using the Cox model.ResultsRisk factors for cirrhosis were viral infection in 47%, excessive alcohol consumption in 45% and MASLD in 13%. In the whole cohort, 27% had 1 MRF, 23% had 2 MRF, 15% had 3 MRF and 6% had 4 MRF. Median PFS and OS were 6.5 and 15.6 months, respectively, and similar in patients with or without MASLD in Log rank analysis. The number of MRF or MALSD was not associated with PFS or OS in the univariate analysis. Factors associated with PFS in multivariate analysis included ALBI grade 3 (HR = 1.60, p = .03), AFP (HR = 1.01, p = .01) and metastasis (HR = 1.77, p < .001). During follow‐up, 10% of patients experienced immune‐related adverse events, with age and female gender, but not MRF or MASLD, as independent predictors.ConclusionOur study suggests that the presence of MASLD or the number of MRF did not lead to worse outcomes in advanced HCC patients treated with AtezoBev.

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“…55,83,84 Moreover, the KEGG enrichment results indicated a high enrichment of the NAFLD pathway in the A1A3 comparison. NAFLD has been reported to be associated with obesity and a sedentary lifestyle, 85 and disruption of circadian rhythms has also been linked to NAFLD. 86,87 Thus, our data suggested that the metabolic pattern in the liver warrants attention, as ABX mice exposed to irregular LD cycles may experience energy and lipid metabolism disorders.…”

Section: Different Ld Cycles Had Varying Impacts On Innate Immune Fun...mentioning

confidence: 99%

Homeostatic crosstalk among gut microbiome, hypothalamic and hepatic circadian clock oscillations, immunity and metabolism in response to different light–dark cycles: A multiomics study

Zhen,

Wang,

et al. 2023

Journal of Pineal Research

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The accelerated pace of life at present time has resulted in tremendous alterations in living patterns. Changes in diet and eating patterns, in particular, coupled with irregular light–dark (LD) cycles will further induce circadian misalignment and lead to disease. Emerging data has highlighted the regulatory effects of diet and eating patterns on the host‐microbe interactions with the circadian clock (CC), immunity, and metabolism. Herein, we studied how LD cycles regulate the homeostatic crosstalk among the gut microbiome (GM), hypothalamic and hepatic CC oscillations, and immunity and metabolism using multiomics approaches. Our data demonstrated that central CC oscillations lost rhythmicity under irregular LD cycles, but LD cycles had minimal effects on diurnal expression of peripheral CC genes in the liver including Bmal1. We further demonstrated that the GM could regulate hepatic circadian rhythms under irregular LD cycles, the candidate bacteria including Limosilactobacillus, Actinomyces, Veillonella, Prevotella, Campylobacter, Faecalibacterium, Kingella, and Clostridia vadinBB60 et al. A comparative transcriptomic study of innate immune genes indicated that different LD cycles had varying effects on immune functions, while irregular LD cycles had greater impacts on hepatic innate immune functions than those in the hypothalamus. Extreme LD cycle alterations (LD0/24 and LD24/0) had worse impacts than slight alterations (LD8/16 and LD16/8), and led to gut dysbiosis in mice receiving antibiotics. Metabolome data also demonstrated that hepatic tryptophan metabolism mediated the homeostatic crosstalk among GM‐liver–brain axis in response to different LD cycles. These research findings highlighted that GM could regulate immune and metabolic disorders induced by circadian dysregulation. Further, the data provided potential targets for developing probiotics for individuals with circadian disruption such as shift workers.

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Role of immune responses in the development of NAFLD-associated liver cancer and prospects for therapeutic modulation

Cited by 30 publications

References 193 publications

Diagnostic value of sphingolipid metabolism-related genes CD37 and CXCL9 in nonalcoholic fatty liver disease

Diagnostic value of sphingolipid metabolism-related genes CD37 and CXCL9 in nonalcoholic fatty liver disease

No correlation between MASLD and poor outcome of Atezolizumab‐Bevacizumab therapy in patients with advanced HCC

Homeostatic crosstalk among gut microbiome, hypothalamic and hepatic circadian clock oscillations, immunity and metabolism in response to different light–dark cycles: A multiomics study

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