Assessing current models of metabolic dysfunction-associated steatotic liver disease: proposing an organoid-based approach for modeling disease progression
OA Version
Citation
Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is one of the leading causes of liver disease in the developed world with an ever-increasing prevalence worldwide. There are numerous risk factors associated with the development of MASLD that stem from downstream effects of obesity, adipose tissue dysfunction, excessive lipid delivery to the liver, and more. MASLD exists on a spectrum ranging from hepatic lipid accumulation known as simple steatosis without inflammation to a stage known as Metabolic Dysfunction-Associated Steatohepatitis (MASH) that includes steatosis, inflammation, and varying degrees of fibrosis. This stage, without removal of stressors, has the potential to develop into cirrhosis which may lead to either liver failure or to the development of hepatocellular carcinoma. Although early stages of MASLD are typically asymptomatic, the later stages, including MASH and severe fibrosis, have detrimental effects on liver histology and functionality, eventually leading to mortality. Despite the disease’s increasing prevalence and poor outcomes, there are currently no FDA-approved treatment plans for MASLD. The lack of treatment options is due to limitations of existing in vitro and in vivo modeling systems and their inability to faithfully recapitulate MASLD’s complexity. This review will investigate the benefits and shortcomings of the various modeling system currently used. In vivo models were found to stray too far from the genetic profile of humans making it difficult to translate finding associated with treatment methods from these models to humans. It was also discovered that 2D and 3D non-organoid models are limited in their capacity to exhibit late stages of disease progression. The models that most closely resembled the disease characteristics and progression were 3D organoids composed of parenchymal and non-parenchymal liver cell types. A new model was created based on the successes of these 3D organoid models was proposed that has the potential to recapitulate MASLD fully and providing a platform for therapeutic testing.
Description
2025
License
Attribution 4.0 International