Hepatology Communications最新文献

Background: Schistosomiasis is a parasitic disease that significantly endangers human health and hampers social development. The accumulation of eggs in the liver can lead to granuloma formation and liver fibrosis. Investigating the immune mechanisms involved may reveal new therapeutic targets for schistosomiasis.

Methods: We collected liver cells from both schistosome-infected mice with fibrotic livers and healthy mice for single-cell sequencing, which allowed us to explore the heterogeneity of immune cells in the fibrotic livers and to use ligand-receptor analysis to examine intercellular communication.

Results: Single-cell sequencing showed significant upregulation of the CXCL16-CXCR6 axis in the fibrotic livers of schistosome-infected mice. Macrophages were the primary source of CXCL16, while CXCR6 was predominantly expressed in T cells. CD4+ T cells and CD8+ T cells were significantly increased in the livers of schistosomiasis, as well as CXCR6 in CD4+T cells and CD8+ T cells. Among different T-cell subsets, Th2 cells primarily expressed the chemokine receptor CXCR6. In CXCR6KO mice, we observed a reduced granuloma area and diminished liver fibrosis. CD4+ T cells were notably lower in the livers of CXCR6KO mice compared to wild-type mice, although there were no significant differences in CD8+ T cells and NKT cells. Furthermore, Th2 cells in the livers of CXCR6KO mice were markedly reduced, along with significant decreases in IL-13, IL-5, and IL-4 levels. In vitro, CXCR6 was significantly upregulated under Th2-polarizing conditions.

Conclusions: Th2 cells are recruited to the liver via the CXCL16-CXCR6 axis, promoting granuloma formation and liver fibrosis in schistosomiasis. The CXCR6 pathway holds potential as a therapeutic target for treating schistosome-associated liver fibrosis.

Background: Metabolic dysfunction-associated fatty liver disease and steatotic liver disease (SLD) have emerged as one of the fastest-growing liver complications over recent decades; this study evaluated trends in SLD prevalence among Chinese adults and its variation across demographic groups.

Methods: A multicenter, retrospective study analyzed health examination data from 600,536 Chinese adults across 10 provinces between 2015 and 2023. Participants (≥18 y) with complete data on age, sex, weight, waist circumference, ultrasound, and biochemical tests were included. SLD was defined as hepatic steatosis with at least 1 metabolic disorder. Age-adjusted SLD prevalence was calculated using direct standardization, and trends were assessed through Joinpoint regression. Logistic regression models examined associations between SLD and demographic/metabolic factors.

Results: Of 501,017 participants (mean age: 43.39±12.89 y, 54.8% male), the age-standardized SLD prevalence rose from 36.24% in 2015 to 48.11% in 2023 (estimated annual percentage change=3.38, p=0.002). Metabolic dysfunction-associated SLD (MASLD) prevalence also increased from 30.01% to 43.17% (estimated annual percentage change=4.48, p<0.001). Subgroup analysis revealed significant increases in individuals aged 18-40, and higher prevalence in older adults, with the highest risk in those aged 41-64. Males had a higher risk than females (53.0% vs. 18.6%, adjusted prevalence ratio=1.97). Participants from North China had a higher risk of both SLD and MASLD compared with South China. Laborers had a lower risk of SLD compared with farmers, while administrative personnel had a higher risk of MASLD.

Conclusions: The prevalence of SLD and MASLD significantly increased from 2015 to 2023, with notable variations across demographic groups, highlighting the need for targeted public health strategies to address the growing burden of SLD in China.

Despite its proven effectiveness in treating liver failure, liver transplantation is often impractical due to its high surgical risks involved and the limited availability of donor organs. Blood purification technologies used in non-bioartificial liver (NBAL) systems have improved clinical cure rates, but they do not substitute for the complex biosynthesis, detoxification, metabolism, and biological transformation roles of the liver. To overcome these challenges brought by NBAL systems, bioartificial liver (BAL) systems have been developed with repeated optimization of both hepatocyte sources and bioreactors to emulate a "fully functional liver"." Large biomedical research centers are eager to conduct clinical trials on the developing BAL systems to validate their safety and efficacy, and eventually bring BAL systems to market for clinical practice. Notably, the successful xenotransplantation of genetically modified porcine livers has provided valuable insights for the novel BAL system design. Chinese researchers have established a progressive series of world-first milestones in pig-to-human liver transplantation. Attempts to create genetically modified porcine BAL systems are promising to explore a path for solving the problem of seeking the most ideal cell sources and bioreactors. This review outlines the current clinical application of artificial liver support systems and summarizes the innovative advancements in BAL technology. Prospects of genetically modified porcine BAL systems are adequately discussed, with the expectation that multidisciplinary collaboration in BAL research will yield more promising therapeutic options for liver failure.

Endoscopic procedures have been integral to the management of patients with liver disease, primarily focusing on luminal interventions such as variceal band ligation. Since the introduction of endoscopic ultrasound, the breadth of procedures has rapidly expanded, leading to the emergence of a new field known as endoscopic hepatology or "endohepatology." This domain integrates endoscopic diagnostic and therapeutic techniques, particularly those which are endoscopic ultrasound-based, into hepatology practice. The comprehensive nature of endohepatology has revolutionized patient care by facilitating a streamlined yet comprehensive approach that enhances efficacy, reduces resource utilization and improves patient satisfaction. Patients can now undergo multiple procedures, such as variceal surveillance and endoscopic ultrasound-liver biopsy in a single session. This review explains the current landscape of endohepatology, highlighting established practices, recent technology advancements, and future directions in the field.

Background: Extracellular matrix proteins are tightly linked to cancer progression. HCC frequently arises from chronic liver diseases with varying degrees of parenchymal fibrosis. Herein, we aimed to investigate the roles of secreted lumican, an extracellular matrix proteoglycan, in HCC.

Methods: Lumican expression in clinical liver tissue samples was analyzed. In vitro and in vivo functional assays were performed with cell lines. Co-culture systems were adopted to examine the roles of lumican in the interaction between HCC cells and liver fibroblasts. Downstream mechanisms were interrogated by transcriptomic and proteomic profiling.

Results: Analyses of single-cell RNA-sequencing datasets collectively revealed high lumican expression in liver fibroblasts. Lumican expression was elevated in liver tissues with advanced fibrosis, and a higher lumican level in the non-tumor liver tissue was a poor prognosticator of HCC. Functionally, recombinant human lumican (rhLUM) promoted migration, invasion, and self-renewal of HCC cells, and enhanced angiogenesis in vitro. These effects were abrogated by anti-lumican antibody. The paracrine actions of lumican in the interplay between HCC cells and liver fibroblasts were supported with co-culture models, in which lumican was manipulated by genetic or antibody approaches. In vivo, recombinant lumican promoted neovascularization and tumor incidence. Profiling results revealed the enrichment of Wnt signaling, and mechanistic dissection uncovered the crosstalk between PI3K/AKT and Wnt/β-catenin pathways in rhLUM-treated HCC cells.

Conclusions: Secreted lumican promotes HCC self-renewal, tumor initiation, and progression by activating the AKT/GSK3β/β-catenin signaling cascade. Targeting secreted lumican is a potential therapeutic strategy for HCC.

Background: Immune checkpoint inhibitors combined with antiangiogenic therapy have become the standard of care for advanced HCC, albeit with limited therapeutic benefit. Our previous studies demonstrated the immunomodulatory and antitumor effects of polyIC, a synthetic dsRNA. Here, we compared the efficacy of anti-programmed death ligand 1 (αPD-L1) plus polyIC versus αPD-L1 plus anti-vascular endothelial growth factor (αVEGF) in mouse tumor models.

Methods: We established a primary liver tumor model using hydrodynamic tail vein injection of Ras/Myc oncogenes and a metastasized tumor model via intrasplenic injection of colon cancer cells. Flow cytometry and gene expression analysis were performed to assess immune profiles across treatment groups. Key factors contributing to antitumor efficacy were explored.

Results: In both models, αPD-L1 plus polyIC demonstrated superior antitumor effects relative to αPD-L1 plus αVEGF. Unlike αVEGF, polyIC enhanced the immune response to αPD-L1 by increasing T cell infiltration, T effector memory CD8+ T cells, CD8+ to CD4+ T cell ratio, and CD8+ T cell function. This combination also promoted apoptosis in tumors and the accumulation of conventional dendritic cells and invariant natural killer T cells. In addition, αPD-L1 plus polyIC treatment led to upregulation of cytokines and chemokines, with CCL5 blockade partially reducing the CD8+ to CD4+ T cell ratio and attenuating polyIC-driven antitumor effects.

Conclusions: This preclinical study identifies polyIC as an efficacious adjuvant of αPD-L1 treatment in liver cancer, providing a better strategy to improve immunotherapy outcomes.

Background: Alcohol-associated liver disease (ALD) is a major cause of alcohol-associated mortality. Previously, we identified KDM5B as a sex-specific mediator of ALD development; however, the mechanism behind KDM5B-induced pathological changes is not established.

Methods: Kdm5b flox/flox female mice were fed a western diet and 20% alcohol in the drinking water for 8-16 weeks (WDA). To induce KO, mice received 2×1011 genome copies of AAV8-CMV-Cre, AAV8-TBG-Cre, or AAV8-control. To test the role of myeloid C/EBPβ, Cebpbfl/fl, or Cebpbfl/fl Lyz2-Cre mice were fed WDA for 16 weeks.

Results: We found that Kdm5b KO prevented alcohol-induced liver fibrosis and liver inflammation in female mice. These changes were in part mediated by hepatocyte-to-non-parenchymal cell communication changes. KDM5B in hepatocytes promoted pro-inflammatory and pro-fibrotic changes in liver macrophages, endothelial cells, and stellate cells. Moreover, KDM5B promoted alcohol-induced early increase in EpCAM-positive liver progenitors and loss of liver function at later time points of alcohol feeding. We found that loss of liver function was dependent on a hepatocyte-to-macrophage communication feedback loop. KDM5B in hepatocytes inhibited macrophage C/EBPβ expression, which in turn resulted in loss of the mature KCs phenotype and prevented the ability of KCs to support hepatocyte differentiation, ultimately leading to loss of liver synthetic function.

Conclusions: KDM5B activation in hepatocytes drives pathogenic cell-cell communication, leading to alcohol-induced loss of liver function in ALD.

Background: The urea cycle and pyrimidine synthesis occur mainly in the liver and undergo opposite changes during hepatocarcinogenesis. Argininosuccinate synthase 1 (ASS1) and carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are key enzymes in the urea cycle and pyrimidine synthesis, respectively, and compete for the common substrate, aspartate. Moreover, ASS1 is lowly expressed in certain cancers, while CAD is highly expressed. However, the role of ASS1 and CAD in liver cancer still remains unclear.

Methods: ASS1 and CAD expression in liver cancer were detected by tissue microarrays. Overexpression of ASS1 and CAD was achieved via lentivirus methods. All in vitro experiments were conducted in cells. The interactions of ASS1 and CAD were detected by co-immunoprecipitation (Co-IP) and GST-pull down. The in vivo study was conducted in a BALB/c nude mouse model. Intracellular metabolites were detected by LC-MS/MS.

Results: ASS1 was lowly expressed in liver cancer, while CAD was highly expressed. In patients with recurrent liver cancer, ASS1 and CAD were significantly negatively correlated. Moreover, liver cancer patients with low ASS1 expression and high CAD expression had a poor prognosis. ASS1 and CAD interacted directly and promoted CAD ubiquitination through STUB1. In addition, Overexpression of CAD attenuated the tumor-suppressive effect of ASS1 in liver cancer cells. Pyrimidine supplementation enhanced the growth of liver cancer cells with ASS1 overexpression.

Conclusions: ASS1 deficiency causes an imbalance in the urea cycle and pyrimidine synthesis in liver cancer. ASS1 directly controls the ubiquitination of CAD via STUB1, rather than just competing with aspartate, thereby suppressing liver cancer. Thus, ASS1 has potential as a druggable target in liver cancer.

Background: Sarcopenia, assessed by psoas muscle CT or MRI, predicts adverse outcomes in adults with advanced chronic liver disease (CLD). However, these radiologic techniques are understudied in children. Ultrasound (US) measures of leg muscle quality and quantity potentially offer a novel, safe, and practical means to assess sarcopenia in pediatric patients.

Methods: We prospectively enrolled pediatric patients (age ≤18) with and without CLD. US of the rectus femoris muscle was performed in triplicate for cross-sectional area (CSA), muscle thickness (MT), echogenic intensity (EI), and fascicle length (FL, calculated). Muscle measures were assessed for intra-rater reliability by intraclass correlation coefficients (ICC) and association with CLD, PELD/MELD, and body mass index (BMI) z-score using logistic regression, linear regression, and Pearson correlation, respectively.

Results: Among 156 participants (N=69 CLD, N=85 healthy), reliability was excellent for CSA, MT, and EI, with ICC ranging from 0.946 (95% CI 0.929-0.959) for EI-right to 0.998 (95% CI 0.998-0.999) for CSA-left, and good for FL (right 0.823, 95% CI 0.769-0.866; left 0.768, 95% CI 0.698-0.825). In age-adjusted and sex-adjusted logistic regression, CLD likelihood decreased with increasing MT and FL (per unit increase: OR=0.82, 95% CI 0.71-0.96; OR=0.99, 95% CI 0.97-0.99) and CLD likelihood increased with increasing EI (OR=1.04, 95% CI 1.01-1.08) for right-side measures (but not left-side). Among CLD, all muscle measures, except EI, were positively correlated with BMI z-score and negatively associated with PELD/MELD score after age-adjustment and sex-adjustment.

Conclusions: Pediatric ultrasound of the rectus femoris muscle demonstrates excellent intra-rater reliability, correlates with measures of malnutrition (BMI) and distinguishes CLD from healthy participants. This may offer a novel tool for assessing sarcopenia and liver disease severity in pediatric CLD.