Asking the Right Questions With Animal Models: Methionine- and Choline-Deficient Model in Predicting Adverse Drug Reactions in Human NASH

Abstract

In the past few decades, great conceptual and technological advances have been made in the field of toxicology, but animal model-based research still remains one of the most widely used and readily available tools for furthering our current knowledge. However, animal models are not perfect in predicting all systemic toxicity in humans. Extrapolating animal data to accurately predict human toxicities remains a challenge, and researchers are obligated to question the appropriateness of their chosen animal model. This paper provides an assessment of the utility of the methionine- and choline-deficient (MCD) diet fed animal model in reflecting human nonalcoholic steatohepatitis (NASH) and the potential risks of adverse drug reactions and toxicities that are associated with the disease. As a commonly used NASH model, the MCD model fails to exhibit most metabolic abnormalities in a similar manner to the human disease. The MCD model, on the other hand, closely resembles human NASH histology and reflects signatures of drug transporter alterations in humans. Due to the nature of the MCD model, it should be avoided in studies of NASH pathogenesis, metabolic parameter evaluation, and biomarker identification. But it can be used to accurately predict altered drug disposition due to NASH-associated transporter alterations.

Gender differences in diet-induced steatotic disease in Cyp2b-null mice

“…Both female and male CDAHFD-fed Cyp2b-null mice had down-regulated GO terms related to xenobiotic metabolism ( S4 Fig). Fatty liver and NASH are known to mediate the down-regulation of detoxification enzymes, especially CYPs [51,52]. Cyp2b9, Cyp2b10, and Cyp2b13 were all significantly down-regulated in CDAHFDfed WT females; conversely, Cyp2b9 was significantly up-regulated in WT CDAHFD-fed males compared to their ND-fed counterparts (S4 File).…”

“…The progression of NAFLD to NASH is characterized by inflammation, fibrosis, stress responses, and hepatocellular injury [5]. GO terms related to xenobiotic metabolism were down-regulated in female and male CDAHFD-fed Cyp2b-null mice in comparison to CDAHFD-fed WT mice, which is commonly seen in NASH [51,52]. Interestingly, CDAHFD decreased Cyp2b expression in WT females, but increased Cyp2b expression in WT males.…”

Gamma‐Tocotrienol Attenuates the Hepatic Inflammation and Fibrosis by Suppressing Endoplasmic Reticulum Stress in Mice

“…Another popular dietary NASH model is a methionine‐ and choline‐deficient diet (MCD), which blocks hepatic β‐oxidation and very low‐density lipoprotein (VLDL) secretion, thereby augmenting hepatic oxidative stress, inflammation, and fibrosis without causing systemic insulin resistance (reviewed in ref. []). By using these two different experimental models of NASH, we thoroughly assessed the impact of γT3 supplementation on NAFLD/NASH.…”

Non‐alcoholic fatty liver disease to metabolic dysfunction‐associated fatty liver disease: Conceptual changes for clinicians, researchers and patients

“…Basically, there are two major categories of NAFLD-related animal models: nutrient-deficient models (ie, those on a methioninecholine-deficient [MCD] diet) and those on a choline-deficient L-amino-defined diet, as well animals on a high-fat diet (HFD) and a modified HFD (adding fructose, cholesterol, trans-fats or chemicals to the HFD). 33 34 On the other hand, although HFD mimics the onset and development of NAFLD, it has limitations in the efficient induction of hepatic inflammation or fibrosis, as well as a relatively long induction time. 33,35 The disease heterogeneity that underlies the change from NAFLD to MAFLD reminds us to reflect further on whether it is reasonable to use these animal models to mimic the heterogeneous pathogenesis in human MAFLD.…”

“…However, both nutrient‐deficient models and HFD models have their own inevitable drawbacks. Nutrient‐deficient models only mimic the histological characteristics of NAFLD or NASH, especially hepatic inflammation and fibrosis, without or even in contrast to metabolic profiles of patients with NAFLD or NASH 34 . On the other hand, although HFD mimics the onset and development of NAFLD, it has limitations in the efficient induction of hepatic inflammation or fibrosis, as well as a relatively long induction time 33,35 …”