Hepatology Communications最新文献

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of obesity and type 2 diabetes, can progress to metabolic dysfunction-associated steatohepatitis and fibrosis. MASLD is characterized by elevated hepatic lipid accumulation (steatosis) and insulin resistance. The ketogenic diet (KD), a high-fat, low-carbohydrate diet, induces hepatic insulin resistance and steatosis in animal models through unknown mechanisms.

Methods and results: Herein, we investigated the mechanisms behind KD-induced metabolic dysfunction-associated steatohepatitis and fibrosis at thermoneutrality, identifying upregulated inflammatory and lipogenic pathways, including Il-6, Tnf, Mapk13, Lpl, and Pparg. Given the substantial increase in IL-6 during MASLD progression, we investigated IL-6-gp130 signaling using liver- and adipocyte-specific knockout mice. Liver-specific gp130 deletion failed to prevent KD-induced hepatic steatosis and glucose intolerance. In contrast, adipocyte-specific gp130 deletion significantly reduced KD-induced hepatic steatosis by suppressing lipolysis in white adipose tissue and reducing p-JNK and p-p38 signaling in the liver. In agreement, adipocyte-specific deletion of gp130 protected mice from KD-induced hepatic steatosis in response to recombinant IL-6 treatment.

Conclusions: Our studies demonstrate the importance of adipose tissue-liver crosstalk in mediating MASLD progression and identify adipocyte IL-6-gp130 as a potential therapeutic target.

Background: Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are immune-mediated cholestatic disorders characterized by progressive biliary inflammation and fibrosis, for which treatment options remain limited, underscoring the need for novel therapeutic targets. The leukemia inhibitory factor (LIF) is an IL-6-related cytokine that dysregulates the communication between epithelial cells and extracellular matrices by binding a heterodimeric complex formed by LIF receptor (LIFR) and gp130. The role of the LIF/LIFR system in PSC and PBC and its potential as a therapeutic target remain unclear.

Methods: We investigated LIF/LIFR system alteration in PSC and PBC and assessed the therapeutic potential of LIFR antagonism in a genetic mouse model of PSC (Abcb4-/- mice). Single-cell transcriptomics analyses were performed to evaluate LIF and LIFR expression in human liver samples. Whole liver RNA-seq and immunostaining were used to assess LIF/LIFR levels and correlation with fibrotic and immune markers. The effects of LIFR antagonism were evaluated in vitro using LRI-310, a steroidal LIFR antagonist, on human cholangiocytes, HSCs, endothelial cells, and macrophages. In vivo, LRI-310 was administered to Abcb4-/- mice, and effects on liver injury, cholestasis, fibrosis, leukocyte infiltration, and gene expression were assessed.

Results: LIF expression s enriched in human cholangiocytes, while LIFR is predominantly expressed by HSCs, endothelial cells, and macrophages. Whole liver RNAseq analysis and liver sections immunostaining demonstarted that increased LIF expression correlates with expression of markers of hepatic fibrosis and immune activation in PSC and PBC patients. LRI-310, a steroidal LIFR antagonist, attenuated human cholangiocytes activation and expression of inflammatory mediators, as well as the activation of liver sinusoidal cells and hepatic fibroblasts. In Abcb4-/- mice administration of LRI-310 mitigated liver injury, cholestasis, liver leukocytes infiltration and reduced the expression of biomarkers associated with fibrosis, inflammation, and bile acid dismetabolism.

Conclusion: Cholangiocyte-derived LIF promotes the formation of a pro-inflammatory and pro-fibrotic niche centred on damaged cholangiocytes. LIFR antagonism reverses fibrosis and immune dysregulation in Abcb4-/- mice, supporting the development of anti-LIFR therapies in human cholangiopathies.

Background: Cholangiocarcinoma (CCA) is an aggressive cancer with a poor prognosis. Histopathology evaluation of brushings and biopsies obtained during endoscopic retrograde cholangiopancreatography (ERCP) currently remains the main method of diagnosis, which has limited sensitivity for malignancy detection. Our study aimed to identify human bile-derived biomarkers to improve CCA diagnosis. Bile samples were collected from patients during ERCP for primary sclerosing cholangitis, CCA, or benign biliary disease.

Methods: Bile samples were collected from patients undergoing ERCP for biliary obstruction due to primary sclerosing cholangitis, newly identified malignant strictures concerning for CCA, or benign biliary disease. Using 16S sequencing, metabolomics, and bile acid quantification, we aimed to identify distinctive microbial and metabolite signatures associated with CCA.

Results: Multi-omics analyses revealed distinct microbial and metabolite signatures associated with CCA. From these findings, we identified and validated microbial and metabolite markers capable of accurately detecting CCA with improved sensitivity and specificity for malignancy detection compared to current cytology-based methods.

Conclusions: These findings highlight the potential of multi-omics bile-based diagnostic panels to enhance endoscopic detection of biliary malignancies, offering a promising tool for evaluating indeterminate biliary strictures and advancing precision in ERCP diagnostics.

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.