Evolving insights into MASLD and MASH pathogenesis and treatment
Series edited by Scott L. Friedman
Metabolic dysfunction associated steatotic liver disease (MASLD, formerly called NAFLD) and its more advanced form, metabolic dysfunction associated steatohepatitis (MASH, formerly called NASH) are increasing in prevalence worldwide as the number of individuals with metabolic risk factors rises. These diseases and their adverse sequelae have a formidable economic impact, and there remain large gaps in understanding and treating MASLD/MASH. Series editor Scott Friedman curated this series of expert-led review articles to cover advances and challenges across the spectrum of basic investigation to clinical trials. The reviews will address diagnostic approaches, management strategies specific to adolescent and pregnant individuals, pathobiology, and therapeutic horizons, with the goal of reflecting the heterogeneity seen in disease drivers as well as the affected population.
Articles in series
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.
Authors
Bernd Schnabl, Christopher J. Damman, Rotonya M. Carr
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.
Authors
Vincent L. Chen, Annapurna Kuppa, Antonino Oliveri, Yanhua Chen, Prabhu Ponnandy, Puja B. Patel, Nicholette D. Palmer, Elizabeth K. Speliotes
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)