Obesity and its metabolic complications are highly prevalent and are major health problems in the United States and worldwide. Indeed, obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically, we hypothesize that experimental NAFLD and the consumption of certain types of dietary fat such as poly-unsaturated fatty acids (PUFA) sensitize the liver to VC as a 2nd hit. We therefore propose that that LA metabolites sensitize the liver to VC hepatotoxicity via molecular, organelle, and cellular VC effects (NAFLD mechanisms).
Aim 1. Evaluate the role of OXLAMs in VC-enhanced hepatocyte death in an animal model of NAFLD. Specifically, we will: a) determine the dose response for NAFLD/NAFLD mechanisms following sub-acute VC exposures and the impact of co-exposures with HF/LA diets, b) determine whether the ablation of OXLAMs via 12/15-LO genetic deficiency attenuates VC-induced liver inflammation and injury and the mechanisms involved. This work will be performed in vivo comparing wild-type (WT) to 12/15-LO knockout mice with complementary in vitro models that target 12/15-LO pharmacologically or genetically (e.g., primary cells derived from 12/15-LO KO mice). Mechanistic endpoints based on preliminary data will include mitochondrial dysfunction, hepatocyte death (necrosis vs. apoptosis), ER stress and metabolism/ bioenergetics impacting steatosis/cell survival.
The aims of this R03 build on my K01 research and extend that project. However, here we are building on that foundation to leverage new questions in investigating the role of a specific fat type (and its oxidized metabolites) that is prevalent in the US. This focus s distinct and unique from my K01 research, but will complement it very aptly. This proposal is consistent with the goals of NIDDK to investigate the causes/consequences of obesity.
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 diet induced obesity (i.e., non-alcoholic fatty liver disease). The project will focus on the interaction of vinyl chloride and specific dietary faty acids in experimental NAFLD.
