# Molecular mechanisms of drug-induced liver injury

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $356,460

## Abstract

Project Summary/Abstract
Drug-induced liver toxicity is a common cause of liver injury accounting for approximately one-half of the cases
of acute liver failure. Currently there is no effective treatment for acute liver failure aside from liver
transplantation, which remains a very difficult surgery with a multitude of possible complications and a high
clinical and financial cost. Associated with acute liver failure are serious non-hepatic consequences, such as
impaired renal and brain function, which negatively impacts patient survival. Therefore, gaining greater
understanding into the molecular pathology contributing to the progression and complications from acute liver
failure could lead to an improvement in patient care, quality of life and a reduction in medical expenditures. We
have previously shown that there is increased expression and secretion of transforming growth factor β1
(TGFβ) from hepatocytes in a mouse model of acute liver failure and that this increase in circulating TGFβ can
increase blood brain barrier permeability and contribute to the resulting neurological complications. The
objective of this proposal is to investigate the downstream consequences of aberrant TGFβ signaling on drug-
induced hepatotoxicity and the development of hepatic encephalopathy with a specific emphasis on IGF1
signaling. Based upon strong preliminary data, we propose the novel central hypothesis that during acute liver
failure, aberrant hepatic TGFβ signaling suppresses both circulating and central bioavailability of IGF1 via
differential mechanisms, and strategies to restore IGF1 levels can be hepatoprotective and neuroprotective.
Two specific aims have been designed to test this working hypothesis: 1) Aberrant hepatic TGFβ results in
increased IGF1 degradation and clearance from the periphery and contributes to hepatocyte cell death; and 2)
Increased circulating TGFβ contributes to the development of hepatic encephalopathy by downregulation of
neuronal IGF1 expression and a subsequent increase in neuroinflammation. The completion of the proposed
studies will provide greater understanding into the molecular pathology contributing to acute liver failure and its
complications, which would lead to the identification of novel therapeutic targets that could greatly benefit the
US healthcare system by improving patient morbidity and mortality, quality of life, and reducing medical
expenditures.

## Key facts

- **NIH application ID:** 9948490
- **Project number:** 5R01DK112803-03
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Sharon DeMorrow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,460
- **Award type:** 5
- **Project period:** 2018-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948490

## Citation

> US National Institutes of Health, RePORTER application 9948490, Molecular mechanisms of drug-induced liver injury (5R01DK112803-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9948490. Licensed CC0.

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