Transcriptomics-driven metabolic pathway analysis reveals similar alterations in lipid metabolism in mouse MASH model and human.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease worldwide, and can rapidly progress to metabolic dysfunction-associated steatohepatitis (MASH). Accurate preclinical models and methodologies are needed to understand underlying metabolic mechanisms and develop treatment strategies. Through meta-analysis of currently proposed mouse models, we hypothesized that a diet- and chemical-induced MASH model closely resembles the observed lipid metabolism alterations in humans.

METHODS: We developed transcriptomics-driven metabolic pathway analysis (TDMPA), a method to aid in the evaluation of metabolic resemblance. TDMPA uses genome-scale metabolic models to calculate enzymatic reaction perturbations from gene expression data. We performed TDMPA to score and compare metabolic pathway alterations in MASH mouse models to human MASH signatures. We used an already-established WD+CCl4-induced MASH model and performed functional assays and lipidomics to confirm TDMPA findings.

RESULTS: Both human MASH and mouse models exhibit numerous altered metabolic pathways, including triglyceride biosynthesis, fatty acid beta-oxidation, bile acid biosynthesis, cholesterol metabolism, and oxidative phosphorylation. We confirm a significant reduction in mitochondrial functions and bioenergetics, as well as in acylcarnitines for the mouse model. We identify a wide range of lipid species within the most perturbed pathways predicted by TDMPA. Triglycerides, phospholipids, and bile acids are increased significantly in mouse MASH liver, confirming our initial observations.

CONCLUSIONS: We introduce TDMPA, a methodology for evaluating metabolic pathway alterations in metabolic disorders. By comparing metabolic signatures that typify human MASH, we show a good metabolic resemblance of the WD+CCl4 mouse model. Our presented approach provides a valuable tool for defining metabolic space to aid experimental design for assessing metabolism.