The problem. Alcohol-associated liver disease (ALD) generally describes a spectrum of alcohol-related liver injuries and is one of the major underlying causes for hepatic steatosis. The progression of the disease is a globally rising health concern: if untreated, it eventually hits a “point of no return” and ultimately manifests in hepatocellular carcinoma, a leading cause of cancer deaths worldwide.
The challenge. Currently, diagnosis of ALD relies on a combination of the patient’s history with clinical, histological and laboratory findings. However, ALD detection can be challenging as (a) there is no single test confirming the diagnosis, (b) patients may not be very open about their actual alcohol consumption and (c) clinical manifestations may be absent or subtle in early ALD. Therefore, it is key to establish reliable parameters that both improve early diagnosis and facilitate prognosis of ALD progression in more advanced and severe cases to select the best therapeutic approach for each patient.Consequently, there is an urgent need for reliable models of human liver responses to disease-relevant challenges that not only capture the spectrum of the metabolic, inflammatory, and fibrotic responses found in patients, but also recapitulate the dynamics of the tissue microenvironment and cell-cell interactions. So far, common cell culture or animal models have however been unable to mirror systemic effects induced by alcohol in humans.
The solution. In the current study, HPC PI Janna Nawroth and her team advanced their previously published Liver-Chip for drug toxicity screening and engineered an ALD Liver-Chip model to analyze early events in human-relevant alcohol-induced steatosis using alcohol concentrations comparable to those found in the blood of patients. Importantly, the ALD-Chip recapitulates critical disease signs such as intracellular lipid accumulation, oxidative stress, and mis-regulation of cholesterol synthesis. Moreover, the research team showcases the systems sensitivity to the two-hit injury described in alcoholic steatohepatitis as well as its ability to model recovery of early injury after alcohol abstinence.
The outlook. The system provides a promising platform toward modeling of human ALD and studying clinically relevant metabolic events including ethanol metabolism, lipogenesis, biliary function, and oxidative stress. The rapid and multimodal response of the ALD Liver-Chip to ethanol will be beneficial for fast, cost-effective go/no-go decisions in drug development studies in the future.