Obesity and its metabolic complications are major health problems in the United States and worldwide. A major disease associated with obesity is non-alcoholic fatty liver disease (NAFLD). Indeed, obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically, we hypothesize that experimental NAFLD sensitizes the liver to VC as a 2nd hit. Recent studies indicate that intestinal barrier function and GI tract flora play a key role in the development of NAFLD. Supplementation with probiotics has been shown to decrease induced gut permeability and liver injury. We therefore propose that VC, via altering intracellular signaling cascades, impairs barrier function integrity in NAFLD and that probiotic supplementation [Lactobacillus rhamnosus Gorbach-Goldin (LGG)] will attenuate these effects.
Aim 1. To test the hypothesis that VC exposure exacerbates liver injury caused by HFD. It is well-known that liver injury is increased by high fat (HFD) diet. It has been shown that VC is hepatotoxic. We propose here that VC exposure will exacerbate liver injury caused by experimental NAFLD (HFD) in mice.
Sub aims will determine: a) the minimal low dose VC exposure conditions that exacerbate fatty liver due to HFD;b) potential mechanisms by which VC exposure enhances liver damage caused HFD.
Aim 2. To determine mechanisms by which VC accentuates fatty liver disease caused by HFD. It is known that there is a critical crosstalk between the GI tract, the adipose tissue and the liver tha plays an important role in the development of NAFLD (i.e., the 'gut-liver-adipose axis'). The purpose of this Aim is to determine the effect of VC metabolites on responses in in vitro paradigms of the gut-liver-adipose axis.
Sub aims will characterize the response of: a) hepatocytes to cytotoxic stimuli, b) response of macrophages to inflammatory stimuli, and c) stimulus of adipocytes to produce adipogenic mediators.
Aim 3. To test the hypothesis that VC exposure exacerbates intestinal permeability caused by HFD. It is known that intestinal permeability is increased after HFD feeding. The barrier function of the intestinal epithelium is also dependent on the gut microbiota profile. Probiotic microorganisms have been shown to improve barrier integrity of the intestinal epithelium. We propose here that VC exposure will exacerbate gut permeability due to HFD in mice and that gut microbiota play an important role in gut permeability and VC-induced toxicity in HF-fed mice. We will further determine if probiotics [e.g., lactobacillus rhamnosus GG (LGG)] will decrease VC-induced toxicity in HF-fed mice via improvement of gut permeability and TJ integrity.
Sub aims will determine: a) the combined effect of VC and HFD on intestinal integrity in vivo (mice) and in vitro (Caco-2 cells);b) the effct of VC and dietary fatty acids on mRNA and surface expression of key tight junction proteins and the role of SAPK signaling in this process in Caco-2 cells;c) if HFD and VC synergistically impair TJ barrier functions in vivo;and d) the protective effect of probiotic LGG on HFD and VC-induced gut permeability.

Public Health Relevance

We propose that vinyl chloride exposure, even below levels that are overtly hepatotoxic, may increase the stimulated inflammatory response in the liver, potentially adding another risk factor to the development of liver disease associated with obesity (i.e., non-alcoholic fatty liver disease). The project will focus on the individual and combined effects of vinyl chloride and diet on gut-liver-adipose axis in experimental NAFLD.

Agency
National Institute of Health (NIH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK096042-02
Application #
8641352
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Louisville
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40202