Journal of Clinical and Translational Hepatology最新文献

Background and aims: Liver iron overload can induce hepatic expression of bone morphogenic protein (BMP) 6 and activate the BMP/SMAD pathway. However, serum iron overload can also activate SMAD but does not induce BMP6 expression. Therefore, the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear. This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway.

Methods: A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin (Holo-Tf). A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days. Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin.

Results: Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6. The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression; specifically, SMURF1 expression dramatically decreased when the serum iron concentration was increased. Additionally, the expression of SMURF1 substrates, which are important molecules involved in the transduction of BMP/SMAD signaling, was significantly upregulated. Furthermore, in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload.

Conclusions: SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload.

Background and aims: The impact of the characteristics of extrahepatic organ failure (EHOF) including the onset time, number, type, and sequence on the prognosis of acute-on-chronic liver failure (ACLF) patients remains unknown. This study aimed to identify the association between the characteristics of EHOF and the prognosis of ACLF patients.

Methods: ACLF subjects enrolled at six hospitals in China were included in the analysis. The risk of mortality based on the characteristics of EHOF was evaluated. Survival of study groups was compared by Kaplan-Meier analysis and log-rank tests.

Results: A total of 736 patients with ACLF were included. EHOF was observed in 402 patients (54.6%), of which 295 (73.4%) developed single EHOF (SEHOF) and 107 (26.6%) developed multiple EHOF (MEHOF). The most commonly observed EHOF was coagulation failure (47.0%), followed by renal (13.0%), brain (4.9%), respiratory (4.3%), and circulatory (2.3%) failure. Survival analysis found that MEHOF or SEHOF patients with brain failure had a worse prognosis. However, no significant outcome was found in the analysis of the effect of onset time and sequence of failed organs on prognosis. Patients were further divided into three risk subgroups by the EHOF characteristics. Kaplan-Meier analysis showed that risk stratification resulted in the differentiation of patients with different risks of mortality both in the training and validation cohorts.

Conclusions: The mortality of ACLF patients was determined by the number and type, but not the onset time and sequence of EHOF. Risk stratification applicable to clinical practice was established.

Background and aims: Targeted therapy and immunotherapy have emerged as treatment options for hepatocellular carcinoma (HCC) in recent years. The significance of serine and glycine metabolism in various cancers is widely acknowledged. This study aims to investigate their correlation with the prognosis and tumor immune microenvironment (TIME) of HCC.

Methods: Based on the public database, different subtypes were identified by cluster analysis, and the prognostic model was constructed through regression analysis. The gene expression omnibus (GEO) data set was used as the validation set to verify the performance of the model. The survival curve evaluated prognostic ability. CIBERSORT was used to evaluate the level of immune cell infiltration, and maftools analyzed the mutations. DsigDB screened small molecule compounds related to prognostic genes.

Results: HCC was found to have two distinct subtypes. Subsequently, we constructed a risk score prognostic model through regression analysis based on serine and glycine metabolism-related genes (SGMGs). A nomogram was constructed based on risk scores and other clinical factors. HCC patients with a higher risk score showed a poor prognosis, and there were significant differences in immune cell infiltration between the high- and low-risk groups. In addition, three potential drugs associated with prognostic genes, streptozocin, norfloxacin, and hydrocotarnine, were identified.

Conclusions: This study investigated the expression patterns of SGMGs and their relationship with tumor characteristics, resulting in the development of a novel model for predicting the prognosis of HCC patients. The study provides a reference for clinical prognosis prediction and treatment of HCC patients.

Hepatocyte nuclear factor 1β (HNF1β) is essential for biliary development, while its genetic defect triggers the dysplasia of interlobular bile ducts, leading to life-threatening hepatitis and cholestasis. To date, this disorder has mainly been documented in neonates. Here, we report a case of cholestasis in an adult patient caused by a de novo HNF1β mutation. A liver biopsy revealed remarkable shrinkage of the portal area accompanied by a decrease or absence of interlobular bile ducts, veins, and arteries in the portal area. Our case showed that an HNF1β defect could induce late-onset cholestasis with paucity of the portal area in adulthood.

[This corrects the article DOI: 10.14218/JCTH.2021.00474.].

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global population. About 20% have a normal body mass index (BMI) and a variant known as lean NAFLD. Unlike typical NAFLD cases associated with obesity and diabetes, lean NAFLD causes liver disease by mechanisms not related to excess weight or insulin resistance. Genetic disorders are among the major factors in developing lean NAFLD, and genome-wide association studies have identified several genes associated with the condition. This review aims to increase awareness by describing the genetic markers linked to NAFLD and the defects involved in developing lean NAFLD.