From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights

Abstract

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.

Problems and Challenges Associated with Renaming Non-alcoholic Fatty Liver Disease to Metabolic Associated Fatty Liver Disease

“…It is necessary to have a deeper understanding of the pathogenesis of fatty liver to promote the development of anti-MAFLD drugs by layering patients, so that each subgroup can benefit from different pharmacological interventions. [ 84 ] Therefore, in early preclinical disease modeling and drug testing, there is a need to develop human-based in vitro models that accurately reflect the different disease subgroups of MAFLD. In addition to cell sources and in vitro disease triggers, each cell culture system has its own specific advantages and limitations when model exit in vitro , [ 85 ] and these characteristics should be incorporated into the design to reduce failure in later clinical studies.…”

Associations between Intake of Different Types of Vegetables and Metabolic Dysfunction- associated Fatty Liver Disease: A Population-based Study

“…Previous studies conducted on HFD-induced animal models of MAFLD have identi ed reduced mitochondrial quality and increased production of growth differentiation factor 15 as potential contributors to the development of MAFLD [9][10][11] . In vitro models, such as primary hepatocytes, hSKP-HPC, iPSC-derived hepatocyte-like cells, HepaRG, and others, are commonly exposed to substances such as glucose, insulin, free fatty acids, TNF-α, IL-1β, or TGF-β to simulate the development of speci c MAFLD subtypes 12 . In these in vitro models, in ammation and brosis are recognized as crucial mechanisms for inducing MAFLD models 13,14 .…”