# Hepatocyte Metabolic Stress Response to Alcoholic Fatty Liver

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $238,445

## Abstract

Abstract
 Alcoholic liver disease (ALD) is one of the most prevalent chronic liver diseases, accounting for more than
half-million deaths worldwide each year. To date, there exist no effective medical interventions; thereby, posing
a serious threat to public health.
 ALD represents a broad-spectrum hepatic disorder from alcoholic fatty liver (AFL), alcoholic steatohepatitis
(ASH) to cirrhosis, the development of which is largely determined by the duration, quantity, and pattern of
substance abuse. AFL, the 1st stage of ALD, is characterized by the massive accumulation of macrovesicular
lipid droplets in hepatocytes without histological features of inflammation. AFL develops as soon as 2 weeks of
alcohol abuse and can also undergo a rapid and complete resolution upon abstinence. However, if abstinence
cannot be achieved, AFL, in turn, serves as the foundation for the development of advanced stages of ALD such
as ASH and cirrhosis, which are associated with extremely high mortality and morbidity rate as well as poor
reversibility even with long-term abstinence. With the opportunity to efficiently mitigate the disease burden of
ALD, AFL represents an attractive therapeutic target. To this end, furthering our understanding of AFL
pathophysiology serves as a critical milestone.
 In this study, we established a novel in vitro study model of AFL with a highly physiological culture system
of terminally differentiated human hepatocyte (HH), then applied for the elucidation of hepatocyte-intrinsic
response to the metabolic stress inflicted by AFL. Cellular response to metabolic stress is a coordinated
adaptation process obligatory for homeostatic maintenance; thus, the failure leads to cell injury. While the
induction of transcriptome changes is an undoubtedly important process in stress response, the synthesis of
respective proteins is ultimately required to execute the designated gene functions. Consequently, we conducted
an integrative analysis of polysome profiling and mRNA-sequencing to elucidate the concordance between
transcriptome change and mRNAs translated by ribosomes. Our analysis revealed that AFL induces a significant
dysregulation of translatome, suggesting that the transcriptome change is discordantly processed at the protein
translation machinery. This observation led to our hypothesis that “AFL dysregulation of translatome results in a
global alteration of the proteome, which acts in concert to impair the stress response and leads to the cytotoxicity.”
 Accordingly, this exploratory proposal is designed to elucidate the mechanism and significance of
translatome alteration as the critical pathophysiology of AFL through the following specific aims: Aim 1:
Determine the molecular mechanism of dysregulated translatome in HH of AFL, and Aim 2: Define the correlation
between transcriptome, translatome and quantitative proteomics of AFL HH. The successful completion of the
proposed studies will provide unique and novel insights on AFL pathophysi...

## Key facts

- **NIH application ID:** 10905904
- **Project number:** 1R21AA031412-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Takeshi Saito
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $238,445
- **Award type:** 1
- **Project period:** 2024-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905904

## Citation

> US National Institutes of Health, RePORTER application 10905904, Hepatocyte Metabolic Stress Response to Alcoholic Fatty Liver (1R21AA031412-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10905904. Licensed CC0.

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