An Experimental DUAL Model of Advanced Liver Damage

Abstract

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. (Hepatology Communications 2021;0:1-18). Excessive alcohol drinking is a leading cause of chronic liver disease and accounts for up to 60%-80% of liver-related mortality in Europe. (1) These data become even more relevant considering that alcohol-associated liver disease (ALD) receives only about 5% of the attention in the field of hepatology. (2) The principal fact that only about 6%-30% of heavy drinkers develop cirrhosis indicates that additional factors modulate the risk of ALD progression. (1) Clinical observations commonly suggest a wide individual susceptibility, and indicate several risk factors for ALD including drinking patterns, female gender, genetic background, cigarette smoking, occupational hazards, and hepatotropic viruses. Obesity and metabolic syndrome (MS) represent another important group of risk factors that accelerate fibrosis

The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent

“…Dysregulation of MCJ was further confirmed using the DUAL dietary model by WB and gene expression (Figure 1C, Supplemental Figure 1b, http:// links.lww.com/HEP/C648). [16] In light of these results, we aimed to understand the mechanism by which the expression of Mcj is regulated after alcohol consumption. Mcj has been previously reported to be epigenetically regulated in NAFLD.…”

Effects of Moderate Alcohol Consumption in Non-Alcoholic Fatty Liver Disease

“…In an experimental approach, Benedé-Ubieto et al have developed a preclinical DUAL model in mice (alcohol-associated liver disease plus MAFLD), which mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis. Hence, it could serve as a preclinical tool for the development of therapeutic approaches [42].…”

A Western diet with alcohol in drinking water recapitulates features of alcohol‐associated liver disease in mice

“…While the WDA model differs considerably from Lieber-DeCarli and Tsukamoto-French models of ALD, several prior studies have also examined the effects of alcohol in drinking water, combined with various diets on liver pathology. Several of these studies added alcohol to diets already known to produce a NASH-like liver injury and showed enhancement of both inflammation and fibrosis by the added alcohol (Benedé-Ubieto et al, 2021;Sengupta et al, 2021).…”