Immune cells and their derived microRNA-enriched extracellular vesicles in nonalcoholic fatty liver diseases: Novel therapeutic targets

Liu, Yang; Hao, Yawen; Boeckmans, Joost; Rodrigues, Robim Marcelino; He, Yong

doi:10.1016/j.pharmthera.2023.108353

Cited by 11 publications

(6 citation statements)

References 165 publications

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“…According to the dominant viewpoint, the crucial factor in causing liver in ammation in NASH patients is the inherent immune mechanisms involved. However, increasing evidence indicates that immune system adaptability also plays a role in causing in ammation in the liver [51]. Our analysis suggested that the presence of CD3 on CD4 + and CD8 dim Tregs, which are associated with adaptive immunity, constitutes a risk factor for MAFLD.…”

Section: Discussionmentioning

confidence: 63%

Immune cells and blood lipids mediation: a Mendelian randomization study on metabolic dysfunction-associated fatty liver disease

Shen,

Liu,

Huang

et al. 2024

Preprint

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Background: The current understanding of the relationship between immune cells and metabolic dysfunction-associated fatty liver disease (MAFLD) is limited. The purpose of this study was to examine the causal role played by immune cells in MAFLD. Methods: To investigate the causal association between immune cells and MAFLD, two-sample Mendelian randomization (MR) studies were conducted. Summary statistics were obtained from genome-wide association studies (GWASs) of 731 immune traits (4 types and 7 panels) and from the two largest meta-GWASs of MAFLD. Thorough reverse and sensitivity analyses were utilized to validate the strength of the findings. Mediation MR analyses were performed to investigate the potential mediating effects of various MAFLD risk factors, such as blood lipids, on the relationship between immune traits and MAFLD. Results: We found that genetically predicted higher CD25 expression on IgD- CD38dim B cells (OR = 0.93, 95% CI = 0.88–0.99) was associated with a lower risk of developing MAFLD. The proportion of genetically predicted CD25 on IgD- CD38dim B cells mediated by high-density lipoprotein cholesterol (HDL-C) was 2.21% and that on Apolipoprotein A1 is 1.91%. During the reverse analysis of the significant impact of NAFLD on immunophenotype, the leukocyte AC TBNK (OR = 1.66, 95% CI = 1.22 ~ 2.27) was identified. Conclusion: Our study provides genetic evidence regarding the role of CD25 on IgD- CD38dim B cells in MAFLD mediated by blood lipids and supports a causal association between various immune cells and MAFLD.

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Section: Discussionmentioning

confidence: 63%

Immune cells and blood lipids mediation: a Mendelian randomization study on metabolic dysfunction-associated fatty liver disease

Shen,

Liu,

Huang

et al. 2024

Preprint

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“…Generally, miRNAs have multiple target genes and play a regulatory role by inhibiting the translation of mRNA 29 . To elucidate the mechanism by which miR-144 promotes liver fibrosis progression, the enrichment of miR-144 predicted target genes (TargetScan, https://www.targetscan.org/mmu_80/ ) was determined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.…”

Section: Resultsmentioning

confidence: 99%

Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells

Hao,

Song,

et al. 2024

Int. J. Biol. Sci.

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Background & Aims : Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl 4 ) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro . Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A , and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.

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“…By engineering EV cargo, researchers can tailor their molecular composition and functional properties to target specific cellular pathways or disease processes. This approach holds promise for the development of novel therapeutics for a wide range of diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, by exploiting the natural delivery capabilities of EVs [ 82 83 84 85 86 87 88 89 ].…”

Section: B Ioengineering Approaches For Manipulating Extrac...mentioning

confidence: 99%

Extracellular vesicles: Function, resilience, biomarker, bioengineering, and clinical implications

Sun,

Chang

2024

Tzu Chi Medical Journal

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Extracellular vesicles (EVs) have emerged as key players in intercellular communication, disease pathology, and therapeutic innovation. Initially overlooked as cellular debris, EVs are now recognized as vital mediators of cell-to-cell communication, ferrying a cargo of proteins, nucleic acids, and lipids, providing cellular resilience in response to stresses. This review provides a comprehensive overview of EVs, focusing on their role as biomarkers in disease diagnosis, their functional significance in physiological and pathological processes, and the potential of bioengineering for therapeutic applications. EVs offer a promising avenue for noninvasive disease diagnosis and monitoring, reflecting the physiological state of originating cells. Their diagnostic potential spans a spectrum of diseases, including cancer, cardiovascular disorders, neurodegenerative diseases, and infectious diseases. Moreover, their presence in bodily fluids such as blood, urine, and cerebrospinal fluid enhances their diagnostic utility, presenting advantages over traditional methods. Beyond diagnostics, EVs mediate crucial roles in intercellular communication, facilitating the transfer of bioactive molecules between cells. This communication modulates various physiological processes such as tissue regeneration, immune modulation, and neuronal communication. Dysregulation of EV-mediated communication is implicated in diseases such as cancer, immune disorders, and neurodegenerative diseases, highlighting their therapeutic potential. Bioengineering techniques offer avenues for manipulating EVs for therapeutic applications, from isolation and purification to engineering cargo and targeted delivery systems. These approaches hold promise for developing novel therapeutics tailored to specific diseases, revolutionizing personalized medicine. However, challenges such as standardization, scalability, and regulatory approval need addressing for successful clinical translation. Overall, EVs represent a dynamic frontier in biomedical research with vast potential for diagnostics, therapeutics, and personalized medicine.

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Immune cells and their derived microRNA-enriched extracellular vesicles in nonalcoholic fatty liver diseases: Novel therapeutic targets

Cited by 11 publications

References 165 publications

Immune cells and blood lipids mediation: a Mendelian randomization study on metabolic dysfunction-associated fatty liver disease

Immune cells and blood lipids mediation: a Mendelian randomization study on metabolic dysfunction-associated fatty liver disease

Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells

Extracellular vesicles: Function, resilience, biomarker, bioengineering, and clinical implications

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