Rodent models and metabolomics in non-alcoholic fatty liver disease: What can we learn?

Abstract

Non-alcoholic fatty liver disease (NAFLD) prevalence has increased drastically in recent decades, affecting up to 25% of the world’s population. NAFLD is a spectrum of different diseases that starts with asymptomatic steatosis and continues with development of an inflammatory response called steatohepatitis, which can progress to fibrosis. Several molecular and metabolic changes are required for the hepatocyte to finally vary its function; hence a “multiple hit” hypothesis seems a more accurate proposal. Previous studies and current knowledge suggest that in most cases, NAFLD initiates and progresses through most of nine hallmarks of the disease, although the triggers and mechanisms for these can vary widely. The use of animal models remains crucial for understanding the disease and for developing tools based on biological knowledge. Among certain requirements to be met, a good model must imitate certain aspects of the human NAFLD disorder, be reliable and reproducible, have low mortality, and be compatible with a simple and feasible method. Metabolism studies in these models provides a direct reflection of the workings of the cell and may be a useful approach to better understand the initiation and progression of the disease. Metabolomics seems a valid tool for studying metabolic pathways and crosstalk between organs affected in animal models of NAFLD and for the discovery and validation of relevant biomarkers with biological understanding. In this review, we provide a brief introduction to NAFLD hallmarks, the five groups of animal models available for studying NAFLD and the potential role of metabolomics in the study of experimental NAFLD.

Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice

“…Alternatively, diets deficient or low in specific nutrients, such as methionine and choline, are also common. Many different iterations of these diets have been investigated, and each produce varying degrees of specific features of NAFLD pathology ( Martin-Grau et al, 2022 ). High-fat diets in mice are reported to induce steatosis and some inflammation and increase the liver damage biomarkers alanine transaminase (ALT) and aspartate transaminase, which are common features in NAFLD patients ( Kubota et al, 2013 ).…”

“…Chemical-induced approaches to model NAFLD attempt to rapidly reproduce specific pathologic features of NAFLD, such as inflammation, steatosis, and fibrosis. Similar to the MCD diet, a limitation of these chemical approaches is the inability to reproduce metabolic features of NAFLD ( Martin-Grau et al, 2022 ). We selected tunicamycin treatment because it produces a NASH-like phenotype and causes ER stress, which occurs in NAFLD and may be related to changes in OATP1B expression.…”

“…Similar to the MCD diet, a limitation to these chemical approaches is the inability to reproduce metabolic features of NAFLD (Martin-Grau et al, 2022). We selected tunicamycin treatment because it produces a NASH-like phenotype and causes ER stress, which occurs in NAFLD and may be related to changes in OATP1B expression.…”

“…Alternatively, diets deficient or low in specific nutrients, such as methionine and choline, are also common. Many different iterations of these diets have been investigated and each produce varying degrees of specific features of NAFLD pathology(Martin-Grau et al, 2022). High fat diets in mice are…”