Open AccessAn Experimental DUAL Model of Advanced Liver Damage
Author(s) -
BenedéUbieto Raquel,
EstévezVázquez Olga,
Guo Feifei,
Chen Chaobo,
Singh Youvika,
Nakaya Helder I.,
Gómez del Moral Manuel,
LamasPaz Arantza,
Morán Laura,
LópezAlcántara Nuria,
Reissing Johanna,
Bruns Tony,
Avila Matías A.,
Santamaría Eva,
Mazariegos Marina S.,
Woitok Marius Maximilian,
Haas Ute,
Zheng Kang,
Juárez Ignacio,
MartínVilla José Manuel,
Asensio Iris,
Vaquero Javier,
Peligros Maria Isabel,
Argemi Josepmaria,
Bataller Ramón,
Ampuero Javier,
Romero Gómez Manuel,
Trautwein Christian,
Liedtke Christian,
Bañares Rafael,
Cubero Francisco Javier,
Nevzorova Yulia A.
Publication year - 2021
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1698
Subject(s) - steatohepatitis , steatosis , fatty liver , fibrosis , medicine , endocrinology , inflammation , adipose tissue , liver disease , biology , pathology , disease
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.