The LIDPAD Mouse Model Captures the Multisystem Interactions and Extrahepatic Complications in MASLD.
Zun Siong LowDamien ChuaHong Sheng ChengRachel TeeWei Ren TanChristopher BallNorliza Binte Esmail SahibSer Sue NgJing QuYingzi LiuHaiyu HongChaonong CaiNandini Chilagondanahalli Lakshmi RaoAileen WeeMark Dhinesh MuthiahZoë BichlerBarbara MickelsonMei Suen KongVanessa Shiyun TayZhuang YanJiapeng ChenAik Seng NgYun Sheng YipMarcus Ivan Gerard VosNicole Ashley TanDao Liang LimDebbie Xiu En LimManesh ChittezhathJadegoud YaligarSanjay Kumar VermaHarish PoptaniXue Li GuanSambasivam Sendhil VelanYusuf AliLiang LiNguan Soon TanWalter WahliPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an impending global health challenge. Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet-induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16 weeks. These findings reveal gut-liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut-pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic-guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease-associated molecular signatures between the human MASLD and LIDPAD model, affirm the model's relevance and potential for driving therapeutic development.