The LIDPAD Mouse Model Captures the Multisystem Interactions and Extrahepatic Complications in MASLD

Zun Siong Low ¹, Damien Chua ¹, Hong Sheng Cheng ¹, Rachel Tee ¹, Wei Ren Tan ¹, Christopher Ball ², Norliza Binte Esmail Sahib ¹, Ser Sue Ng ¹, Jing Qu ³, Yingzi Liu ⁴, Haiyu Hong ⁵, Chaonong Cai ⁵, Nandini Chilagondanahalli Lakshmi Rao ⁶, Aileen Wee ⁷, Mark Dhinesh Muthiah ^8 9 10, Zoë Bichler ¹, Barbara Mickelson ¹¹, Mei Suen Kong ¹, Vanessa Shiyun Tay ¹, Zhuang Yan ¹, Jiapeng Chen ¹, Aik Seng Ng ¹², Yun Sheng Yip ¹, Marcus Ivan Gerard Vos ¹, Nicole Ashley Tan ¹³, Dao Liang Lim ¹³, Debbie Xiu En Lim ¹, Manesh Chittezhath ¹, Jadegoud Yaligar ^2 14, Sanjay Kumar Verma ², Harish Poptani ¹⁵, Xue Li Guan ¹, Sambasivam Sendhil Velan ^2 9 14, Yusuf Ali ^1 16, Liang Li ¹⁷, Nguan Soon Tan ^1 13, Walter Wahli ^1 18 19

. 2024 Jul 1:e2404326.

• PMID: 38952069
• DOI: 10.1002/advs.202404326

Abstract

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.