An Experimental DUAL Model of Advanced Liver Damage
Raquel Benedé-Ubieto 1 2 , Olga Estévez-Vázquez 1 2 , Feifei Guo 2 , Chaobo Chen 2 , Youvika Singh 3 , Helder I Nakaya 3 4 , Manuel Gómez Del Moral 5 , Arantza Lamas-Paz 2 , Laura Morán 2 , Nuria López-Alcántara 2 6 , Johanna Reissing 7 , Tony Bruns 7 , Matías A Avila 8 9 10 , Eva Santamaría 8 9 , Marina S Mazariegos 2 , Marius Maximilian Woitok 7 , Ute Haas 7 , Kang Zheng 2 11 12 , Ignacio Juárez 2 , José Manuel Martín-Villa 2 13 , Iris Asensio 9 13 14 , Javier Vaquero 9 13 14 , Maria Isabel Peligros 15 , Josepmaria Argemi 16 17 18 , Ramón Bataller 16 19 , Javier Ampuero 9 20 , Manuel Romero Gómez 9 20 , Christian Trautwein 7 , Christian Liedtke 7 , Rafael Bañares 2 9 13 14 , Francisco Javier Cubero 2 11 , Yulia A Nevzorova 2 7 11
Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases.
However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model).
Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation.
Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis.
Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue.
Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.