# Role of Hepatocyte TLR4 in Alcohol-induced Steatohepatitis and Insulin Resistance

> **NIH NIH K01** · UNIVERSITY OF TEXAS DALLAS · 2020 · $149,472

## Abstract

Abstract
 Excessive alcohol drinking-induced chronic liver disease has been recognized as a serious health problem
in the United States. Increasing evidence suggests that inflammation plays an essential role in the
development of alcoholic liver disease (ALD). In particular, the potent inflammatory response produced by the
interactions between gut-derived lipopolysaccharide (LPS) and its cell surface receptor, Toll-like receptor 4
(TLR4), greatly contribute to alcohol-induced liver injury. However, the exact TLR4-expressing cell type that
mediates this effect is largely unknown. Recently, we and others reported that hepatocyte TLR4 regulates
obesity-related chronic inflammation, insulin resistance, and nonalcoholic liver disease. Furthermore, our
preliminary data showed that mice lacking hepatocyte TLR4 had attenuated alcohol-induced early liver injury
and reduced inflammation in white adipose tissue. In contrast, mice with TLR4 reactivation in hepatocyte
accumulated more triglyceride content in the liver after chronic alcohol drinking. These findings support the
potential role of hepatocyte TLR4 in mediating alcohol-induced steatohepatitis and insulin resistance. We will
take advantage of our two unique mouse models that can selectively ablate and reactivate TLR4 expression in
hepatocytes, respectively, to pursue the following specific aims. In specific aim 1, we will determine the role of
hepatocyte TLR4 in the development of alcoholic steatohepatitis. We will use the mice lacking TLR4
expression specifically in hepatocyte to test the hypothesis that hepatocyte TLR4 is required for the
development of alcoholic steatohepatitis induced by acute-on-chronic ethanol drinking. In specific aim 2, we
will feed mice an ethanol-containing liquid diet chronically up to 8 weeks. We will test the hypothesis that
hepatocyte TLR4 is required for the development of alcohol-induced insulin resistance. In specific aim 3, we
will use a TLR4 reactivatable mouse model that can restore endogenous TLR4 expression specifically in
hepatocytes to determine the sufficiency of hepatocyte TLR4 in alcohol-related steatohepatitis and insulin
resistance. These studies will greatly enhance our knowledge of the regulatory role of hepatocyte TLR4 in
alcoholic liver damage and associated metabolic disorders and facilitate the development of new anti-ALD
therapies.

## Key facts

- **NIH application ID:** 10294073
- **Project number:** 7K01AA024809-05
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** Lin Jia
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $149,472
- **Award type:** 7
- **Project period:** 2017-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10294073

## Citation

> US National Institutes of Health, RePORTER application 10294073, Role of Hepatocyte TLR4 in Alcohol-induced Steatohepatitis and Insulin Resistance (7K01AA024809-05). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10294073. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*