Modeling Alcoholic Liver Disease in a Human Liver-Chip

Abstract

Fatty liver disease (FLD) is a major public health burden that affects up to 30% of people in Western countries and leads to progressive liver injury, comorbidities, and increased mortality. One risk factor for developing FLD is alcohol consumption, which is growing in prevalence worldwide. There is an urgent need for human-relevant preclinical models to improve our understanding of FLD progression to steatohepatitis in alcoholic liver disease (ALD) and to develop sensitive noninvasive diagnostics and therapies of FLD in general. Here, by leveraging a tri-culture human Liver-Chip with biomimetic hepatic sinusoids and bile canaliculi, we achieve the first in vitro modeling of ALD that uses human relevant blood alcohol concentrations (BAC) and affords multimodal profiling of clinically relevant endpoints. Our ALD Liver-Chip recapitulates established FLD markers in response to ethanol in a concentration-dependent manner, including lipid accumulation and oxidative stress. The ALD Liver-Chip also supports the study of secondary insults common in patients with advanced ALD, such as high blood endotoxin levels due to alcohol-associated increased intestinal permeability and barrier dysfunction. Moreover, the ALD Liver-Chip enables the measurement of structural changes of the hepatic bile canaliculi network as a novel in vitro quantitative readout of alcoholic liver toxicity, and the co-culture of human stellate cells to study their role in FLD progression and liver fibrosis. In summary, we report the development of a human ALD Liver-Chip as a new platform for modeling the progression of alcohol-induced liver injury and fatty liver disease with direct translation to clinical research.