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Mutations in the GABA A receptor have been implicated in alcohol dependence in humans. In this study, the authors show that mice with mutations in the beta 1 subunit of the GABA A receptor exhibit spontaneous GABA A channel opening and preferentially consume alcohol, working harder to access it.

A combination of animal studies, data from a clinical trial and insights from an observational cohort suggest that, in individuals with metabolic dysfunction-associated steatohepatitis, semaglutide improves liver histology by reverting patient proteomes to better mimic the proteome of individuals without the disease.

Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease with a substantial burden worldwide. In this Consensus Statement, a global multidisciplinary group of experts develop consensus statements and recommendations addressing a broad range of topics on NAFLD to raise awareness and spur action.

Non-alcoholic fatty liver disease (NAFLD) is characterized by increased hepatic triglyceride content (HTGC) in the absence of high alcohol consumption. Here the authors show that a genetic variant in TM6SF2, which is known to be associated with HTGC, is a clinically relevant modifier of hepatic fibrogenesis and increases the risk of progressive NAFLD.

NAFLD, the hepatic manifestation of the metabolic syndrome, is a multifactorial condition — environmental factors influence an inherited genetic risk. Stender et al. now describe the additive effect of obesity and NAFLD-associated genetic polymorphisms on steatosis, elevated serum alanine aminotransferase levels and cirrhosis, remarkably illustrating the principle of gene–environment interactions.

NAFLD is a complex disease. Considerable variability exists in the severity and risk of morbidity and mortality among individuals with NAFLD, which could be influenced by genetic and environmental factors. Here, the authors discuss the latest knowledge on the genetics of NAFLD and how this genetic variation might determine disease phenotype and progression.

NAFLD is becoming much more common, and will soon be the major underlying aetiology for liver transplantation. This article discusses the evidence that NAFLD is a multisystem disease and outlines the factors that determine interindividual variation in the development and progression of NAFLD.

Govaere et al. integrate circulating protein data from more than 300 patients with non-alcoholic fatty liver disease (NAFLD) with transcriptomics and develop a non-invasive diagnostics tool to identify patients with at-risk NAFLD based on body mass index, type 2 diabetes status and four circulating proteins.

In a prospective, regulatory-grade study of assistance to pathologists in MASH histology scoring, AIM-MASH-assisted reads by expert MASH pathologists were superior to unassisted reads and decreased inter-reader variability.

The LITMUS consortium provides a resource of rodent MASLD models benchmarked against metabolic, histologic and transcriptomic features that are relevant for human MASLD. The work is useful for selecting relevant rodent models for studying this common disease.

Metabolic and alcohol-related liver disease presents challenges in clinical trials due to complex pathophysiology. This Review discusses noninvasive imaging, serum biomarkers and adaptive designs as modalities to enhance patient-centric end points, aiming to refine diagnostics and improve drug development.

In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), underlies many cases of hepatocellular carcinoma (HCC). In this Review, the authors discuss NAFLD-associated HCC, including its epidemiology, key features that promote hepatocarcinogenesis and the management of HCC in patients with obesity.

A multiancestry genome-wide association study of chronic alanine aminotransferase elevation identifies candidate risk loci for nonalcoholic fatty liver disease, with replication in external cohorts defined by histology or imaging.

Non-alcoholic fatty liver disease is more common among older individuals. Here, the authors show that senescent cells in the liver promote fat accumulation and steatosis in the liver, and that clearance of senescent cells reduces hepatic steatosis in old, obese or diabetic mice.

Hepatic bone morphogenetic protein 8b expression is shown to be induced in NASH to drive wound healing responses and NASH progression by promoting inflammatory pathways in hepatic stellate cells and, more broadly, in the liver parenchyma.

IgA⁺ B cells expressing programmed death ligand 1 (PD-L1) and interleukin 10 accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease where they promote the progression to hepatocellular carcinoma by limiting the local activation of PD-1-expressing CD8⁺ T cells.

Derek Mann and his colleagues have found that experimental induction of liver fibrosis in male rats results in an epigenetic modification of the chromatin in their sperm such that their offspring have a more mild wound-healing response to hepatic fibrogenic insults. The mechanism responsible for this phenomenon is not clear, but it seems to involve a yet unidentified soluble factor released by myofibroblasts that act on either the germ cells or mature sperm.

The practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD are not well defined. Here, the authors develop and validate two diagnostic tools: a stepwise stratification algorithm including a cirrhosis group, and a risk prediction chart providing a personalized assessment of the individual probability of cirrhosis.

NAFLD is growing in prevalence worldwide, and has emerged as a leading cause of end-stage liver disease in many countries. In this Review, the authors describe the global epidemiology of NAFLD, discuss associated risk factors and outline challenges for screening and management.

Metabolic dysfunction-associated steatohepatitis (MASH), a primary cause of chronic liver disease (CLD), often leads to advanced CLD stages such as cirrhosis. This Roadmap summarizes the current landscape and challenges of MASH-related compensated cirrhosis clinical trials and explores a way forward for future studies.

In this Perspective, the authors discuss the various mouse preclinical models that are available for the study of non-alcoholic steatohepatitis (NASH) and NASH-induced hepatocellular carcinoma, and provide advice on reporting practices and how to select the most appropriate model.

Sena et al. survey European clinical research sites that could potentially serve as the foundation for a MASH integrated research platform and clinical research network. Respondents generally believe that a MASH platform trial could benefit patients and are interested in participating, though securing industry funding is identified as a priority.

Metabolomics and lipidomics approaches are being used to identify biomarkers for nonalcoholic fatty liver disease (NAFLD). This Review discusses the application of metabolomics and lipidomics in clinical studies and in the identification of key metabolic pathway alterations in NAFLD.

There is a need for effective models of care for patients with non-alcoholic fatty liver disease (NAFLD). In this Expert Recommendation, Lazarus et al. discuss seven examples of comprehensive NAFLD models of care and produce eight recommendations aimed at policy-makers and practitioners.

Cardiovascular disease is the leading cause of death in NAFLD. In this Review, the authors explore the evidence that NAFLD affects not only the coronary arteries but also all other cardiac structures, thereby potentially increasing risk of cardiomyopathy, cardiac arrhythmias, conduction defects and valvular calcification.