# A human Liver-on-a-Chip model for studying alcohol-associated liver disease

> **NIH NIH R21** · CEDARS-SINAI MEDICAL CENTER · 2023 · $438,375

## Abstract

Project Summary
Alcohol-associated liver disease (ALD) is still a serious health concern as 47% of liver-related death is due to
excessive alcohol consumption. Despite of extensive research efforts, no effective therapy has been
developed for ALD. One of the reasons suspending the development of effective therapy for ALD could be the
lack of model systems suitable to study human relevant molecular mechanism of ALD. The current available
cell culture systems and rodent ALD models do not recapitulate an ALD condition relevant in humans. To
investigate more physiological experimental conditions in vitro, we established a Liver-on-a-chip model, which
is a 3D in vitro hepatic micro-physiological system designed to simulate the in vivo functional conditions of liver
tissues by co-culturing human-originated cells. We recently engineered a human liver-on-a-chip model suitable
for investigating the underlying molecular mechanism of ALD in vitro based on the fact that human primary
hepatocytes on liver-on-a-chip express higher levels of alcohol-metabolizing enzymes, such as alcohol
dehydrogenase 1 (ADH1), aldehyde dehydrogenase 2 (ALDH2), and CYP2E1, compared with monolayer
cultured hepatocytes. In this proposal, based on our new preliminary data using a liver-on-a-chip model, we
hypothesis that, in addition to hepatocytes, liver sinusoidal endothelial cells (LSECs) and aldehyde metabolism
in LSECs play important roles in regulating ethanol-induced liver damage. We will investigate whether
ALDH2 in LSECs contributes to the protection for the development of ALD through acetaldehyde
metabolism using a Liver-on-a-chip system (Aim 1). Because fibrosis is a risk factor for high-mortality of
alcoholic hepatitis (AH), we further hypothesize that fibrotic changes in hepatic stellate cells (HSCs) and
senescent changes in LSECs contribute to the increased susceptibility of ethanol-induced liver damage. We
will investigate whether senescent LSECs and fibrotic HSCs contribute to the development of the
microenvironment of severe ALD in cirrhotic livers as the mechanism of the development of severe AH in
cirrhosis using a Liver-on-a-chip system (Aim 2). The proposed study will provide new insight into the role of
ALDH2 expression and acetaldehyde metabolism in various liver cells in the progression of ethanol-induced
liver damage, and provide the basis for the use of a liver-on-a-chip model as a new in vitro experimental tool to
study ALD with human relevant conditions.

## Key facts

- **NIH application ID:** 10752839
- **Project number:** 1R21AA031173-01
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** EKIHIRO SEKI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $438,375
- **Award type:** 1
- **Project period:** 2023-09-11 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752839

## Citation

> US National Institutes of Health, RePORTER application 10752839, A human Liver-on-a-Chip model for studying alcohol-associated liver disease (1R21AA031173-01). Retrieved via AI Analytics 2026-08-01 from https://api.ai-analytics.org/grant/nih/10752839. Licensed CC0.

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