Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm

Abstract

Fatty liver disease is an emerging contributor to disease burden worldwide. The past decades of work established the heterogeneous nature of non-alcoholic fatty liver disease (NAFLD) etiology and systemic contributions to the pathogenesis of the disease. This called for the proposal of a redefinition in 2020 to that of metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect the current understanding of the disease. To date, several clinical cohort studies comparing NAFLD and MAFLD hint at the relevancy of the new nomenclature in enriching for patients with more severe hepatic injury and extrahepatic comorbidities. However, the underlying systemic pathogenesis is still not fully understood. Preclinical animal models have been imperative in elucidating key biological mechanisms in various contexts, including intrahepatic disease progression, interorgan crosstalk and systemic dysregulation. Furthermore, they are integral in developing novel therapeutics against MAFLD. However, substantial contextual variabilities exist across different models due to the lack of standardization in several aspects. As such, it is crucial to understand the strengths and weaknesses of existing models to better align them to the human condition. In this review, we consolidate the implications arising from the change in nomenclature and summarize MAFLD pathogenesis. Subsequently, we provide an updated evaluation of existing MAFLD preclinical models in alignment with the new definitions and perspectives to improve their translational relevance.

Exploring the dynamic three-dimensional chromatin architecture and transcriptional landscape in goose liver tissues underlying metabolic adaptations induced by a high-fat diet

“…Animal models of NAFLD are predominantly established using high-fat dietary feeding, pharmacological intervention, and genetic modification. These models encompass a diverse range of mammals, spanning monkeys [ 47 ], mice [ 48 ], rats [ 49 ], pigs [ 50 ], rabbits [ 51 ], and geese [ 46 ], with each model offering distinct advantages and holding specific applicability. The goose HFD liver is significantly yellow compared to the dark red liver of the normal-diet group, and lipid droplet deposition has previously been reported in goose livers [ 52 , 53 ].…”

Angiopoietin-like 4 shapes the intrahepatic T-cell landscape via eIF2α signaling during steatohepatitis in diet-induced NAFLD

“…Understanding the network of multisystem interactions requires a physiologically relevant animal model that can mirror the many human NASH features and comorbidities( 34 ). An improved dietinducible liver disease mouse model was established using a refined Liver Disease Progression Aggravation Diet (LIDPAD).…”