The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension

Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) are the leading causes of liver disease worldwide. To identify disease-specific pathomechanisms, we analyzed the lipidome, metabolome and immune cell recruitment in livers in both diseases. Mice harboring ASH or NASH had comparable disease severities regarding mortality rate, neurological behavior, expression of fibrosis marker and albumin levels. Lipid droplet size was higher in NASH than ASH and qualitative differences in the lipidome were mainly based on incorporation of diet-specific fatty acids into triglycerides, phosphatidylcholines and lysophosphatidylcholines. Metabolomic analysis showed downregulated nucleoside levels in both models. Here, the corresponding uremic metabolites were only upregulated in NASH suggesting stronger cellular senescence, which was supported by lower antioxidant levels in NASH as compared to ASH. While altered urea cycle metabolites suggest increased nitric oxide synthesis in both models, in ASH, this depended on increased L-homoarginine levels indicating a cardiovascular response mechanism. Interestingly, only in NASH were the levels of tryptophan and its anti-inflammatory metabolite kynurenine upregulated. Fittingly, high-content immunohistochemistry showed a decreased macrophage recruitment and an increased polarization towards M2-like macrophages in NASH. In conclusion, with comparable disease severity in both models, higher lipid storage, oxidative stress and tryptophan/kynurenine levels were seen in NASH, leading to distinct immune responses.

Aim: This study aimed to identify novel miRNAs (miRs) as regulators of UGT1A gene expression and to evaluate them as potential risk factors for the development of liver fibrosis/cirrhosis. Material...

Background: Obesity and nonalcoholic fatty liver disease (NAFLD) are an increasing health care burden worldwide. Weight loss is currently the best option to alleviate NAFLD and is efficiently achieved by bariatric surgery. Presence of NAFLD seems to be predictive for postoperative weight loss. To date, only few predictive factors for postbariatric weight loss (age, diabetes, psychiatric disorders) are established. Objectives: Since liver fibrosis is the pathogenic driver for the progression of liver disease, we investigated its role in predicting postoperative weight loss. This study focuses on the correlation between fibrosis stage and weight loss. Setting: University and university-affiliated cooperation, Germany. Methods: We used a prospective, single-center cohort study including 164 patients who underwent bariatric surgery with simultaneous liver biopsies. Liver fibrosis was determined histologically according to Kleiner score and noninvasively by APRI and FIB-4 score. Percentage of total body weight loss was calculated at 1-year follow up visit. Results: Thirty-two patients were found without fibrosis, whereas 91 patients showed mild fibrosis (F1), 37 significant fibrosis (F2), and only 4 patients presented advanced fibrosis (F3) at the time of bariatric surgery. Weight loss was similar across different degrees of fibrosis stage. Accordingly, linear regression analysis did not identify predictors of weight loss among fibrosis scores. In multi- variable analysis, age and presence of diabetes showed the strongest predictive value. Conclusions: Baseline presence of fibrosis was not associated with postoperative weight loss, while age and diabetes were independent predictors of weight loss. Bariatric surgery should be applied independently of the fibrosis stage. (Surg Obes Relat Dis 2024;20:759-766.) (c) 2024 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well characterized, the posttranscriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the posttranscriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that ~70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs, enriched in suboptimal codons and bearing short poly(A) tails under normal diet, becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3′ UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by rapid deterioration of organ function in pre-existing chronic liver disease. Patients who develop ACLF within 90 days after decompensation are referred to as pre-ACLF. Known precipitants include bacterial infections and viral hepatitis. However, in 40-60% of patients, the precipitant remains unknown. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are highly prevalent viruses, but their impact on ACLF is unclear. 211 patients (43 ACLF, 16 pre-ACLF, and 152 non-ACLF) of the ACLF-I study and an external validation cohort with 153 patients (39 ACLF, 33 pre-ACLF, and 81 non-ACLF) were included. Sera were analyzed for CMV/EBV DNA (multiplex qPCR), cytokines in 102 ACLF-I samples (multiplex assays), and immunoglobulins in 80 case-control matched ACLF-I and 20 validation cohort patients (immunoassays), and correlated with clinical data. In the ACLF-I group, a higher prevalence of CMV DNAemia (8.9% vs. 25.6%, odds ratio [OR] 3.51, 95% CI 1.47-8.34, p <0.01) and EBV DNAemia (6.6% vs. 16.3%, OR 3.01, 95% CI 1.10-8.62, p <0.05) was observed in ACLF compared to non-ACLF cases, despite the absence of clinical signs of viral infections. 54.8% of DNAemic ACLF patients in the validation cohort had no identified precipitant compared to 26.5% in ACLF patients without DNAemia (p <0.05). CMV was associated with liver failure (p <0.001) and with 90-day mortality (p <0.001) in the regression model. DNAemia was associated with a distinct pattern of inflammatory activity. The results were validated externally. Serological analyses revealed that reactivation rather than primary infection occurred in most cases defined as DNAemic. Presence of CMV/EBV DNAemia in chronic liver disease may contribute to the development of ACLF by exacerbating liver inflammation and impairing hepatocellular function. Despite ACLF being a life-threatening syndrome, the underlying precipitant cannot be identified in 30-40% of cases. As a result, intervention in ACLF development is limited to cases with known precipitants. To our knowledge, this is the first time it is shown that previously undiagnosed CMV and EBV DNAemia might act as a precipitating event inducing ACLF. We propose that routine screening and proper treatment for CMV and EBV in decompensated cirrhotic patients can intervene in ACLF development. This hypothesis needs to be assessed in prospective studies. NCT04975490.