Authors
Arora, S., Katyal, A.
Abstract
BACKGROUND: Existing rodent models of alcoholic liver disease (ALD) often fail to replicate its whole clinical progression, from steatosis to alcoholic hepatitis, and ultimately cirrhosis and overlook key metabolic contributors. Clinically, high-fat diets and gut-derived endotoxins (from enteric dysbiosis) act as additional hits that exacerbate alcohol-induced liver injury. Moreover, alcohol metabolism generates oxidative stress and modifies self-proteins into neo-antigens, potentially triggering immune responses. A model that incorporates these elements is critical for studying ALD pathogenesis and its immunological aspects. METHODS: Male Wistar rats were randomized into four groups. The AL group received alcohol (36% caloric equivalent) and a single LPS dose 24 hours before sacrifice. The AF group was fed a high-fat diet (35% caloric equivalent) for 15 days, then maintained on alcohol and fat. The ALF group was similarly primed with fat, maintained on alcohol and fat, and given LPS before sacrifice. The ICC group served as isocaloric controls. Liver injury was assessed via histology, biochemical markers (AST, ALT, MDA), and serum endotoxin levels. ELISA was used to analyze antibody titers against liver proteins; neoantigens were identified using proteomics. RESULTS: All treated groups showed elevated liver enzymes, MDA, and endotoxin levels, indicating progressive liver damage. The ALF group exhibited the most severe pathology within six weeks, progressing from steatosis to steatohepatitis and fibrosis. In contrast, the AF group showed steatosis alone, and the AL group displayed moderate inflammation. Neoantigens were most abundant in the ALF group. CONCLUSION: We present a novel, rapid-onset triple-hit model of ALD that accurately mimics the full spectrum of the disease. This model enables mechanistic studies on how diet and gut-derived endotoxins contribute to ALD, highlighting the immunogenic potential of alcohol-induced neoantigens.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 12 Nov 2025.
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