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.

Public Health Relevance

Alcoholic liver disease (ALD) contributes significantly to the death and disability in the United States. Particularly, alcoholic hepatitis can progress to fibrosis and cirrhosis, which are life-threatening. In addition, heavy drinking is associated with impaired insulin action. The aim of this proposal is to investigate the requirement and sufficiency of hepatocyte TLR4 in the development of alcoholic steatohepatitis and insulin resistance. The results from this project will provide novel therapeutic strategies for the treatment of ALD and related metabolic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AA024809-03
Application #
9699987
Study Section
National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
Program Officer
Wang, Joe
Project Start
2017-06-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Jia, Lin; Chang, Xiuli; Qian, Shuwen et al. (2018) Hepatocyte toll-like receptor 4 deficiency protects against alcohol-induced fatty liver disease. Mol Metab 14:121-129